New Compounds

ABSTRACT

The present invention relates to compounds of general formula I 
     
       
         
         
             
             
         
       
     
     wherein A, B, D, Y, R 1 , R 2 , R 3 , R 4  and R 5  are defined as in the specification, the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases, which have valuable properties, the preparation thereof, the pharmaceutical compositions containing the pharmacologically effective compounds, the preparation thereof and the use thereof.

The present invention relates to compounds of general formula I

wherein A, B, D, Y, R¹, R², R³, R⁴ and R⁵ are as defined hereinbelow, the enantiomers, diastereomers, mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases, which have valuable properties, the preparation thereof, the pharmaceutical compositions containing the pharmacologically effective compounds, the preparation thereof and the use thereof.

DETAILED DESCRIPTION OF THE INVENTION

In the above general formula I in a first embodiment

-   A denotes a bond, C₁₋₄-alkylene or —CH₂—C(O), -   B denotes a bond, C₁₋₃-alkylene, —O or —C(O), -   D denotes a group of general formulae II

-   Y denotes a C₁₋₆-alkylene group optionally substituted by the group     R², wherein a methylene group may additionally be replaced by Y¹ and     -   Y¹ denotes —O, —S, —S(O), —N(R²), —N(R²)—C(O), —C(O)—N(R²),         —C(O), —CH(aryl), C₃₋₆-cycloalkylene or —S(O)₂—, -   R¹ denotes C₃₋₇-cycloalkyl or aryl, heteroaryl or aryl-C₁₋₃-alkyl,     each of which may be substituted by one, two, three or four groups     R^(1.1), while the groups R^(1.1) may be identical or different and     -   R^(1.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, F₃C, HO,         C₁₋₃-alkyl-O or C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, -   R² denotes H or C₁₋₃-alkyl, while each methylene group may be     substituted by up to two and each methyl group may be substituted by     up to three fluorine atoms, or also denotes H₃C—C(O), -   R³ denotes     -   a) C₁₋₆-alkylene,     -   b) a C₃₋₆-cycloalkylene group mono-, di or trisubstituted by         R^(3.1),     -   c) a C₅₋₇-cycloalkenylene group mono- or disubstituted by         R^(3.1) which is fused to a phenyl ring via the unsaturated         bond,     -   d) —N(R²),     -   e) an arylene group mono- or disubstituted by R^(3.1),     -   f) a heteroarylene group mono- or disubstituted by R^(3.1),     -   g) a saturated 4- to 7-membered heterocyclic ring mono- or         disubstituted by R^(3.1),     -   h) an unsaturated 5- to 7-membered heterocyclic ring mono- or         disubstituted by R^(3.1), which is fused to one or two phenyl         rings via the unsaturated bonds, or     -   i) a saturated 8- to 10-membered aza-heterobicyclic group mono-         or disubstituted by R^(3.1),     -   while the groups R^(3.1) may be identical or different in each         case and     -   R^(3.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, HO, C₁₋₃-alkyl-O or         C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, or -   R³ also denotes —O, if B does not denote the group —O—, -   R⁴ denotes     -   a) —O,     -   b) —C(O)O,     -   c) —C(O)NR²,     -   d) —NR²,     -   e) —NR²—NR²,     -   f) C₃₋₇-cycloalkylene,     -   g) C₁₋₆-alkylene,     -   h) an arylene group mono- or disubstituted by R^(4.1),     -   i) a heteroarylene group mono- or disubstituted by R^(4.1),     -   j) a 4- to 7-membered saturated heterocyclic ring mono- or         disubstituted by R^(4.1),     -   k) a saturated 8- to 10-membered diaza-heterobicyclic group         mono- or disubstituted by R^(4.1),     -   l) a 5- to 7-membered unsaturated heterocyclic ring mono- or         disubstituted by R^(4.1), which is fused to one or two phenyl         rings via the unsaturated bonds, or     -   m) a saturated 9- to 11-membered diaza-spirocyclic group,     -   while the groups R^(4.1) may be identical or different in each         case and     -   R^(4.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, HO, C₁₋₃-alkyl-O or         C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, -   R⁵ denotes H, HO, C₁₋₈-alkyl, a C₃₋₇-cycloalkyl group optionally     substituted by C₁₋₃-alkyl, H₂N, C₁₋₄-alkyl-NH, (C₃₋₆-cycloalkyl)-NH,     (C₁₋₄-alkyl)₂N, (C₁₋₄-alkyl)(C₃₋₆-cycloalkyl)N,     (cyclopropylmethyl)(methyl)N, H₂N—C(O), a phenyl group mono- or     disubstituted by R^(5.1), a heteroaryl group mono- or disubstituted     by R^(5.1) or a 4- to 7-membered saturated heterocyclic ring mono-     or disubstituted by R^(5.1), while the groups R^(5.1) may be     identical or different in each case and     -   R^(5.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, HO, C₁₋₃-alkyl-O,         (C₁₋₃-alkyl)₂N or C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—,         the enantiomers, the diastereomers, the mixtures and the salts         thereof, particularly the physiologically acceptable salts         thereof with organic or inorganic acids or bases.

A second embodiment of the present invention comprises the compounds of the above general formula I, wherein

-   A denotes a bond or C₁₋₄-alkylene, -   B denotes a bond, C₁₋₃-alkylene, —O or —C(O), -   D denotes a group of general formulae II

-   Y denotes a C₁₋₄-alkylene group optionally substituted by the group     R², wherein a methylene group may additionally be replaced by Y¹ and     -   Y¹ denotes —O, —S, —S(O), —N(R²), —N(R²)—C(O), —C(O)—N(R²),         —C(O), —CH(aryl) or —S(O)₂—, -   R¹ denotes C₃₋₇-cycloalkyl or aryl, heteroaryl or aryl-C₁₋₃-alkyl,     each of which may be substituted by one, two, three or four groups     R^(1.1), while the groups R^(1.1) may be identical or different and     -   R^(1.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, HO, C₁₋₃-alkyl-O or         C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, -   R² denotes H or C₁₋₃-alkyl, while each methylene group may be     substituted by up to two and each methyl group may be substituted by     up to three fluorine atoms, -   R³ denotes C₁₋₆-alkylene, an arylene group mono- or disubstituted by     R^(3.1), a heteroarylene group mono- or disubstituted by R^(3.1), a     saturated 4- to 7-membered heterocyclic ring mono- or disubstituted     by R^(3.1) or a unsaturated 5- to 7-membered heterocyclic ring mono-     or disubstituted by R^(3.1), while the groups R^(3.1) may be     identical or different in each case and     -   R^(3.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, HO, C₁₋₃-alkyl-O or         C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, -   R⁴ denotes —O, —C(O)O, —C(O)NR², —NR², —NR²—NR², C₃₋₇-cycloalkylene,     C₁₋₆-alkylene, an arylene group mono- or disubstituted by R^(4.1), a     heteroarylene group mono- or disubstituted by R^(4.1), a 4- to     7-membered saturated heterocyclic ring mono- or disubstituted by     R^(4.1) or a 5- to 7-membered unsaturated heterocyclic ring mono- or     disubstituted by R^(4.1), while the groups R^(4.1) may be identical     or different in each case and     -   R^(4.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, HO, C₁₋₃-alkyl-O or         C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, -   R⁵ denotes H, C₁₋₈-alkyl, a C₃₋₇-cycloalkyl group optionally     substituted by C₁₋₃-alkyl, H₂N, C₁₋₄-alkyl-NH, (C₁₋₄-alkyl)₂N,     H₂N—C(O), a heteroaryl group mono- or disubstituted by R^(5.1) or a     4- to 7-membered saturated heterocyclic ring mono- or disubstituted     by R^(5.1), while the groups R^(5.1) may be identical or different     in each case and     -   R^(5.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, HO, C₁₋₃-alkyl-O or         C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—,         the enantiomers, the diastereomers, the mixtures and the salts         thereof, particularly the physiologically acceptable salts         thereof with organic or inorganic acids or bases.

A third embodiment of the present invention comprises the compounds of the above general formula I, wherein

-   A denotes a bond, C₁₋₄-alkylene or —CH₂—C(O), -   B denotes a bond, C₁₋₂-alkylene, —O or —C(O), -   D denotes a group of general formula II

-   Y denotes C₁₋₄-alkylene or a group selected from

-   R¹ denotes aryl or heteroaryl, each of which may be substituted by     one, two, three or four groups R^(1.1), while the groups R^(1.1) may     be identical or different and     -   R^(1.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, F₃C, HO,         C₁₋₃-alkyl-O or C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, -   R² denotes H, H₃C, H₅C₂, isopropyl, F₃C—CH₂, F₂CH—CH₂ or FH₂C—H₂C, -   R³ denotes C₁₋₄-alkylene, —N(R²) or a group selected from

-   wherein     -   R^(3.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, HO, C₁₋₃-alkyl-O or         C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, or -   R³ also denotes —O, if B does not denote the group —O—, -   R⁴ denotes C₁₋₄-alkylene, C₃₋₇-cycloalkylene, —O or a group selected     from

-   R⁵ denotes H, C₁₋₈-alkyl, C₃₋₇-cycloalkyl, HO, (C₁₋₃-alkyl)-O,     (C₁₋₄-alkyl)-NH, (C₃₋₆-cycloalkyl)-NH, (C₁₋₄-alkyl)₂N,     (C₁₋₄-alkyl)(C₃₋₆-cycloalkyl)N, (cyclopropylmethyl)(methyl)N,     H₂N—C(O), or -   R⁵ denotes a group selected from

the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.

A fourth embodiment of the present invention comprises the compounds of the above general formula I, wherein

-   A denotes a bond or C₁₋₃-alkylene, -   B denotes a bond, C₁₋₂-alkylene, —O or —C(O), -   D denotes a group of general formula II

-   Y denotes C₁₋₄-alkylene or a group selected from

-   R¹ denotes aryl or heteroaryl, each of which may be substituted by     one, two, three or four groups R^(1.1), while the groups R^(1.1) may     be identical or different and     -   R^(1.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, HO, C₁₋₃-alkyl-O or         C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, -   R² denotes H, H₃C, H₅C₂, isopropyl, F₃C—CH₂, F₂CH—CH₂ or FH₂C—H₂C, -   R³ denotes C₁₋₄-alkylene or a group selected from

-   wherein     -   R^(3.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, HO, C₁₋₃-alkyl-O or         C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, -   R⁴ denotes C₁₋₄-alkylene, —O or a group selected from

-   R⁵ denotes H, C₁₋₈-alkyl, C₃₋₇-cycloalkyl, (C₁₋₄-alkyl)-NH,     (C₁₋₄-alkyl)₂N, H₂N—C(O), or -   R⁵ denotes a group selected from

the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.

A fifth embodiment of the present invention comprises the compounds of the above general formula I, wherein

-   A denotes a bond, C₁₋₃-alkylene or —CH₂—C(O), -   B denotes a bond, C₁₋₂-alkylene, —O or —C(O), -   D denotes a group of general formula II

-   Y denotes a group selected from

-   R¹ denotes a group selected from

-   R² denotes H, H₃C, H₅C₂ or FH₂C—H₂C, -   R³ denotes C₁₋₄-alkylene, —NH, —N(CH₃) or a group selected from

-   R³ also denotes —O, if B does not denote the group —O—, -   R⁴ denotes C₁₋₄-alkylene, C₃₋₇-cycloalkylene, —O or a group selected     from

-   R⁵ denotes H, HO, C₁₋₅-alkyl, C₃₋₅-cycloalkyl, H₂N, (C₁₋₂-alkyl)-NH,     (C₃₋₆-cycloalkyl)-NH, (C₁₋₂-alkyl)₂N,     (C₁₋₄-alkyl)(C₃₋₆-cycloalkyl)N, (cyclopropylmethyl)(methyl)N,     H₂N—C(O), or -   R⁵ denotes a group selected from

the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.

A sixth embodiment of the present invention comprises the compounds of the above general formula I, wherein

-   A denotes a bond or C₁₋₃-alkylene, -   B denotes a bond, C₁₋₂-alkylene, —O or —C(O), -   D denotes a group of general formula II

-   Y denotes a group selected from

-   R¹ denotes a group selected from

-   R² denotes H, H₃C, H₅C₂ or FH₂C—H₂C, -   R³ denotes C₁₋₄-alkylene or a group selected from

-   R⁴ denotes C₁₋₄-alkylene, —O or a group selected from

-   R⁵ denotes H, C₁₋₅-alkyl, H₂N, (C₁₋₂-alkyl)-NH, (C₁₋₂-alkyl)₂N,     H₂N—C(O), or -   R⁵ denotes a group selected from

the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.

A seventh embodiment of the present invention comprises the compounds of the above general formula I, wherein A, B, D, Y, R², R³, R⁴ and R⁵ are defined as hereinbefore under the first to sixth embodiments and

-   R¹ denotes the group

the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.

An eighth embodiment of the present invention comprises the compounds of the above general formula I, wherein A, B, D, Y, R², R³, R⁴ and R⁵ are defined as hereinbefore under the first to sixth embodiments and

-   R¹ denotes the group

the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.

A ninth embodiment of the present invention comprises the compounds of the above general formula I, wherein A, B, R¹, R³, R⁴ and R⁵ are defined as hereinbefore under the first to eighth embodiments and

-   -D-Y— together denote a group selected from

and

-   R² denotes H or C₁₋₃-alkyl-,     the enantiomers, the diastereomers, the mixtures and the salts     thereof, particularly the physiologically acceptable salts thereof     with organic or inorganic acids or bases.

A tenth embodiment of the present invention comprises the compounds of the above general formula I, wherein

-   A denotes a bond, -   B denotes a bond, -   -D-Y— together denote a group selected from

and

-   R¹ denotes the group

-   R² denotes H or C₁₋₃-alkyl, while each methylene group may be     substituted by up to two and each methyl group may be substituted by     up to three fluorine atoms, -   R³ denotes a C₄₋₆-cycloalkylene group, -   R⁴ denotes a saturated 6- or 7-membered diaza heterocycle and -   R⁵ denotes C₁₋₃-alkyl or C₃₋₅-cycloalkyl,     the enantiomers, the diastereomers, the mixtures and the salts     thereof, particularly the physiologically acceptable salts thereof     with organic or inorganic acids or bases.

The following are mentioned as examples of most particularly preferred compounds of the above general formula I:

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(579)

(580)

(581)

(582)

(583)

(584)

(585)

(586)

(587)

(588)

(589)

(590)

(591)

(592)

(593)

(594)

(595)

(596)

(597)

(598)

(599)

(600)

(601)

(602)

(603)

(604)

(605)

(606)

(607)

(608)

(609)

(610)

(611)

(612)

(613)

(614)

(615)

(616)

(617)

(618)

(619)

(620)

(621)

(622)

(623)

(624)

(625)

(626)

(627)

(628)

(629)

(630)

(631)

(632)

(633)

(634)

(635)

(636)

(637)

(638)

(639)

(640)

(641)

(642)

(643)

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(645)

(646)

(647)

(648)

(649)

(650)

the enantiomers, the diastereomers, the mixtures and the salts thereof, particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.

TERMS AND DEFINITIONS USED

Unless otherwise stated, all the substituents are independent of one another. If for example there are a plurality of C₁₋₆-alkyl groups as substituents in one group, in the case of three C₁₋₆-alkyl substituents, independently of one another, one may represent methyl, one n-propyl and one tert-butyl.

Within the scope of this application, in the definition of possible substituents, these may also be represented in the form of a structural formula. If present, an asterisk (*) in the structural formula of the substituent is to be understood as being the linking point to the rest of the molecule.

The subject-matter of this invention also includes the compounds according to the invention, including the salts thereof, wherein one or more hydrogen atoms, for example one, two, three, four or five hydrogen atoms, are replaced by deuterium.

By the term “C₁₋₂-alkyl” (including those which are part of other groups) are meant alkyl groups with 1 to 2 carbon atoms, by the term “C₁₋₃-alkyl” are meant branched and unbranched alkyl groups with 1 to 3 carbon atoms, by the term “C₁₋₄-alkyl” are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms, by the term “C₁₋₅-alkyl” are meant branched and unbranched alkyl groups with 1 to 5 carbon atoms, by the term “C₁₋₆-alkyl” are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms and by the term “C₁₋₈-alkyl” are meant branched and unbranched alkyl groups with 1 to 8 carbon atoms. Examples include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, hexyl, heptyl and octyl. The following abbreviations may optionally also be used for the above-mentioned groups: Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. Unless stated otherwise, the definitions propyl, butyl, pentyl, hexyl, heptyl and octyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.

Moreover, the terms mentioned above also include those groups wherein each methylene group may be substituted by up to two fluorine atoms and each methyl group may be substituted by up to three fluorine atoms.

By the term “C₁₋₂-alkylene” are meant branched and unbranched alkylene groups with 1 or 2 carbon atoms, by the term “C₁₋₃-alkylene” (including those which are part of other groups) are meant branched and unbranched alkylene groups with 1 to 3 carbon atoms, by the term “C₁₋₄-alkylene” are meant branched and unbranched alkylene groups with 1 to 4 carbon atoms, by the term “C₁₋₆-alkylene” are meant branched and unbranched alkylene groups with 1 to 6 carbon atoms and by the term “C₂₋₄-alkylene” are meant branched and unbranched alkylene groups with 2 to 4 carbon atoms. Examples include: methylene, ethylene, ethane-1,1-diyl, propylene, propane-2,2-diyl, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene. Unless stated otherwise, the definitions propylene and butylene include all the possible isomeric forms with the same number of carbons. Thus, for example, propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.

In addition, the terms mentioned above also include those groups wherein each methylene group may be substituted by up to two fluorine atoms.

By the term “C₃₋₅-cycloalkyl” are meant cyclic alkyl groups with 3 to 5 carbon atoms, by the term “C₃₋₆-cycloalkyl” are meant cyclic alkyl groups with 3 to 6 carbon atoms and by the term “C₃₋₇-cycloalkyl” (including those which are part of other groups) are meant cyclic alkyl groups with 3 to 7 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless otherwise stated, the cyclic alkyl groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

By the term “C₃₋₆-cycloalkylene” (including those which are part of other groups) are meant cyclic alkylene groups with 3 to 6 carbon atoms, by the term “C₃₋₇-cycloalkylene” are meant cyclic alkylene groups with 3 to 7 carbon atoms and by the term “C₄₋₆-cycloalkylene” are meant cyclic alkylene groups with 4 to 6 carbon atoms. Examples include: cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene or cycloheptylene. Unless otherwise stated, the cyclic alkylene groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine. A C₄- or a C₅-cycloalkylene group may be linked to the remainder of the molecule in the 1,2 position or in the 1,3 position, preferably in the 1,3 position. A C₆- or a C₇-cycloalkylene group may be linked to the remainder of the molecule in the 1,2 position, in the 1,3 position or in the 1,4 position, preferably in the 1,3 position.

By the term “C₅₋₇-cycloalkenylene” (including those which are part of other groups) are meant cyclic alkenyl groups with 5 to 7 carbon atoms, which contain an unsaturated bond and which are fused to a phenyl ring via this unsaturated bond. Examples include: cyclopentenyl, cyclohexenyl or cycloheptenyl:

Unless otherwise stated, the cyclic alkenyl groups may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.

By the term “saturated heterocyclic rings” are meant four, five, six or seven membered heterocyclic rings which may contain one, two or three heteroatoms selected from among oxygen, sulphur and nitrogen. The ring may be attached to the molecule through a carbon atom and/or—if present—through a nitrogen atom or also through two carbon atoms or through two nitrogen atoms. Although it is encompassed by the term “heterocyclic rings”, the term “heterocyclic non-aromatic rings” denotes five, six or seven membered saturated rings. Examples include:

By the term “saturated diaza-heterocycles” are meant six or seven membered heterocyclic rings which contain two nitrogen atoms. The ring is linked to the remainder of the molecule through both nitrogen atoms. Examples include:

By the term “saturated aza-heterobicycles” are meant eight, nine or ten membered heterobicyclic rings which contain a nitrogen atom. The ring is linked to the remainder of the molecule through a carbon atom and the nitrogen atom. Examples include:

By the term “saturated diaza-heterobicycles” are meant eight, nine or ten membered heterobicyclic rings which contain two nitrogen atoms. The ring is linked to the remainder of the molecule through both nitrogen atoms. Examples include:

By the term “unsaturated heterocyclic rings” are meant five-, six- or seven-membered, mono- or diunsaturated heterocyclic rings which may contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen and condensed through the unsaturated bonds with one or two phenyl rings. The heterocyclic ring may be linked to the molecule through a carbon atom and/or—if present—through a nitrogen atom or through two carbon atoms or through two nitrogen atoms. Examples include:

By the term “saturated diaza-spirocycles” are meant nine-, ten- or eleven-membered spirocyclic rings which contain two nitrogen atoms. The spirocyclic group is linked to the remainder of the molecule through the two nitrogen atoms. Examples include:

By the term “aryl” (including those which are part of other groups) are meant aromatic ring systems with 6 or 10 carbon atoms. Examples of these are phenyl, 1-naphthyl or 2-naphthyl; preferred aryl groups are phenyl and 1-naphthyl; the particularly preferred aryl group is phenyl. Unless otherwise stated, the aromatic groups may be substituted by one or more groups selected from among methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, bromine and iodine, while the groups may be identical or different.

By the term “heteroaryl” are meant five- or six-membered heterocyclic aromatic groups or 9-11 membered bicyclic heteroaryl rings, which may contain one, two or three heteroatoms, selected from among oxygen, sulphur and nitrogen, and additionally contain sufficient conjugated double bonds to form an aromatic system. Examples of five- or six-membered heterocyclic aromatic groups are as follows:

Unless otherwise stated, the heteroaryls mentioned previously may be substituted by one or more groups selected from among methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, bromine and iodine, while the groups may be identical or different.

Bicyclic heteroaryl rings may preferably be substituted in the phenyl group.

By the term “arylene” (including those which are part of other groups) are meant aromatic ring systems with 6 or 10 carbon atoms. Examples include: phenylene, 1-naphthylene or 2-naphthylene, the preferred arylene group being phenylene. Unless otherwise stated, the aromatic groups may be substituted by one or more groups selected from among methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, bromine and iodine.

These aromatic ring systems are linked to the rest of the molecule at two places independently of one another through a carbon atom in each case.

By the term “heteroarylene” are meant five- or six-membered heterocyclic aromatic groups or 9-11 membered bicyclic heteroaryl rings which may contain one, two or three heteroatoms selected from among oxygen, sulphur and nitrogen, and additionally sufficient conjugated double bonds to form an aromatic system. These heterocyclic aromatic groups are linked at two points independently of one another either through carbon and/or nitrogen.

The following are examples of five- or six-membered heterocyclic aromatic groups:

Unless otherwise stated, the heteroaromatic groups may be substituted by one or more groups selected from among methyl, ethyl, n-propyl, iso-propyl, tert-butyl, hydroxy, methoxy, trifluoromethoxy, fluorine, chlorine, bromine and iodine. Preferably, the substituents in the above-mentioned 5-10 membered bicyclic heteroaryl rings are in the phenyl ring.

If they contain suitable basic functions, for example amino groups, compounds of general formula I may be converted, particularly for pharmaceutical use, into the physiologically acceptable salts thereof with inorganic or organic acids. Examples of inorganic acids for this purpose include hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulphuric acid, methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid or p-toluenesulphonic acid, while organic acids that may be used include malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid or citric acid. In addition, any tertiary amino groups present in the molecule may be quaternised. Alkyl halides are used for the reaction. According to the invention methyl iodide is preferably used for the quaternisation.

In addition, the compounds of general formula I, if they contain suitable carboxylic acid functions, may if desired be converted into the addition salts thereof with inorganic or organic bases. Examples of inorganic bases include alkali or alkaline earth metal hydroxides, e.g. sodium hydroxide or potassium hydroxide, or carbonates, ammonia, zinc or ammonium hydroxides; examples of organic amines include diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine or dicyclohexylamine.

The compounds according to the invention may be present as racemates, provided that they have only one chiral element, but may also be obtained as pure enantiomers, i.e. in the (R) or (S) form.

However, the application also includes the individual diastereomeric pairs of antipodes or mixtures thereof, which are obtained if there is more than one chiral element in the compounds of general formula I, as well as the individual optically active enantiomers of which the above-mentioned racemates are made up. The invention relates to the compounds in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids—such as for example acid addition salts with hydrohalic acids—for example hydrochloric or hydrobromic acid—or organic acids—such as for example oxalic, fumaric, diglycolic or methanesulphonic acid.

Methods of Preparation

According to the invention the compounds of general formula I are obtained by methods known per se, for example by the following methods:

The linking of carboxylic acids of general formula III shown in Scheme 1 wherein all the groups are as hereinbefore defined, with amines of general formula IV, wherein all the groups are as hereinbefore defined, forming carboxylic acid amides of general formula Ia, wherein all the groups are as hereinbefore defined, may be carried out using conventional methods of amide formation.

The coupling is preferably carried out using methods known from peptide chemistry (cf. e.g. Houben-Weyl, Methoden der Organischen Chemie, Vol. 15/2), for example using carbodiimides such as e.g. dicyclohexylcarbodiimide (DCC), diisopropyl carbodiimide (DIC) or ethyl-(3-dimethylaminopropyl)-carbodiimide, O-(1H-benzotriazol-1-yl)-N,N-N′,N′-tetramethyluronium hexafluorophosphate (HBTU) or tetrafluoroborate (TBTU) or 1H-benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). By adding 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt) the reaction speed can be increased. The couplings are normally carried out with equimolar amounts of the coupling components as well as the coupling reagent in solvents such as dichloromethane, tetrahydrofuran, acetonitrile, dimethyl formamide (DMF), dimethyl acetamide (DMA), N-methylpyrrolidone (NMP) or mixtures thereof and at temperatures between −30° C. and +30° C., preferably −20° C. and +25° C. If necessary, N-ethyl-diisopropylamine (Hünig base) is preferably used as an additional auxiliary base.

An alternative method of attachment consists in converting a carboxylic acid of general formula III, wherein all the groups are as hereinbefore defined, into a carboxylic acid chloride of general formula V, wherein all the groups are as hereinbefore defined, and subsequent reaction with an amine of general formula IV, wherein all the groups are as hereinbefore defined. The synthesis of a carboxylic acid chloride of general formula V is carried out using methods known from the literature (see e.g. Houben-Weyl, Methoden der Organischen Chemie, vol. E5/1).

The carboxylic acids of general formula III used as starting materials, wherein all the groups are as hereinbefore defined, is obtained using methods known per se from the literature, for example by the methods of synthesis shown in Schemes 2 to 7.

The sulphonic acid chlorides of general formula VI, wherein R¹ is as hereinbefore defined, are either known from the literature or commercially obtainable. They are reacted under standard reaction conditions with an amine of general formulae H₂N—R², VIIIa or VIIIb to obtain sulphonic acid amides of general formulae VII, X or XI, wherein R¹ and R² are hereinbefore defined and n denotes a number 1, 2, 3 or 4 and R⁶ denotes a C₁₋₆-alkyl group. The reaction is optionally carried out in the presence of a base such as triethylamine, DIPEA or pyridine and an inert solvent such as dichloromethane or tetrahydrofuran at a temperature of 0° C. to 100° C. with a typical reaction time of one to 24 hours.

The reaction of the sulphonic acid amides of general formula VII with a halide of general formula IX, wherein Hal¹ denotes chlorine or bromine, is carried out using methods known from the literature, for example with the aid of a base such as potassium or sodium carbonate in dimethylformamide or tetrahydrofuran at 0° C. to 100° C.

The hydrolysis of the carboxylic acid esters of general formula XI, wherein R¹ and R² are as hereinbefore defined, n denotes a number 1, 2, 3 or 4 and R⁶ denotes a C₁₋₃-alkyl group, to obtain carboxylic acids of general formula XII, wherein R¹ and R² are as hereinbefore defined and n denotes a number 1, 2, 3 or 4 and R⁶ denotes a C₁₋₃-alkyl group, is carried out under known conditions, for example with lithium or sodium carbonate and water in methanol and/or tetrahydrofuran.

The preparation of sulphonic acid amides of general formula XIV is carried out as described under Scheme 2.

The alkylation of the hydroxyl function of the sulphonic acid amides of general formula XIV, wherein R¹ and R² are as hereinbefore defined with the proviso that R² does not denote a hydrogen atom, and n denotes a number 1, 2, 3 or 4 and R⁶ denotes a C₁₋₃-alkyl group, is carried out under reaction conditions known from the literature, for example under 2-phase conditions using a phase transfer catalyst in the presence of a strong inorganic base such as sodium hydroxide solution or potassium hydroxide solution and in an inert solvent such as toluene at 0° C. to 100° C.

The cleaving of the tert-butylester of general formula XVI, wherein R¹ and R² are as hereinbefore defined, n denotes a number 1, 2, 3 or 4 and R⁶ denotes a C₁₋₃-alkyl group and R⁷ denotes a hydrogen atom or a C₁₋₃-alkyl group, is carried out using methods known from the literature (see e.g. Philip J. Kocieński, Protecting Groups, 3rd Edition, 2005, published by Georg Thieme).

The sulphonation of the hydroxyl function of a compound of general formula XIV, wherein R¹ and R² are as hereinbefore defined, with the proviso that R² does not denote a hydrogen atom, and n denotes a number 1, 2, 3 or 4 and R⁶ denotes a C₁₋₃-alkyl group, with a sulphonic acid chloride of general formula R⁸SO₂Cl, wherein R⁸ denotes a C₁₋₃-alkyl group or a phenyl group optionally substituted by a C₁₋₃-alkyl group, to form compounds of general formula XVIII, wherein all the groups are as hereinbefore defined, is carried out under standard reaction conditions, typically in the presence of a base such as DMAP and/or pyridine and an inert solvent such as dichloromethane or THF at −5° C. to 35° C. A liquid base such as pyridine may be used as the base and solvent simultaneously.

The subsequent alkylation of the amines of general formula VII to form compounds of general formula XIX, wherein R¹ and R² are as hereinbefore defined, n denotes a number 1, 2, 3 or 4 and R⁶ denotes a C₁₋₃-alkyl group and R⁶ denotes a C₁₋₆-alkyl group, is conveniently carried out in a solvent such as toluene, chlorobenzene, dimethylformamide, dimethylsulphoxide (DMSO), dichloromethane, acetonitrile or pyridine, for example at temperatures between 0° C. and 150° C. and conveniently in the presence of bases such as pyridine, triethylamine, DIPEA, potassium carbonate, potassium-tert-butoxide or sodium methoxide, the alkylsulphonate serving as the leaving group.

The hydrolysis of the carboxylic acid esters of general formula XIX to form carboxylic acids of general formula XX is carried out as described under Scheme 2.

The Finkelstein reaction of compounds of general formula XVIII, wherein R¹ and R² are as hereinbefore defined, n denotes a number 1, 2, 3 or 4 and R⁶ denotes a C₁₋₃-alkyl group and R⁸ denotes a C₁₋₃-alkyl group or a phenyl group optionally substituted by a C₁₋₃-alkyl group, to form halides of general formula XXI, wherein R¹ and R² are as hereinbefore defined and n denotes a number 1, 2, 3 or 4 and R⁶ denotes a C₁₋₃-alkyl group, is carried out under known reaction conditions (see e.g. H. Finkelstein, Berichte der Deutschen Chemischen Gesellschaft 43, 1910, 1528).

The subsequent alkylation of the glycine ester is carried out as described under Scheme 4 (R²≠H).

The amino function in the compounds of general formula XXIII is protected by a conventional protective group PG by known methods. The selected protective group is one which can be cleaved under non-hydrogenolytic conditions. A preferred protective group is the Boc group. An overview of the chemistry of protective groups can be found in Theodora W. Greene and Peter G. M. Wuts, Protective Groups in Organic Synthesis, Second Edition, 1991, published by John Wiley and Sons, and in Philip J. Kocienski, Protecting Groups, 3rd Edition, 2005, published by Georg Thieme.

The cleaving of the carboxylic acid esters of general formula XXIII to form carboxylic acids of general formula XXIV is carried out as described under Scheme 2.

The alkylation of a thiol of general formula XXV, wherein n denotes a number 1, 2, 3 or 4 and R⁶ denotes a C₁₋₆-alkyl group, to obtain compounds of general formula XXVI, wherein R¹ and R² are as hereinbefore defined, n denotes a number 1, 2, 3 or 4 and R⁶ denotes a C₁₋₆-alkyl group, is conveniently carried out in a solvent such as toluene, chlorobenzene, DMF, DMSO, dichloromethane, acetonitrile or pyridine, for example at temperatures between 0° C. and 150° C. and conveniently in the presence of bases such as pyridine, triethylamine, DIPEA, potassium carbonate, potassium-tert-butoxide or sodium methoxide, while the alkylsulphonate serves as leaving group.

The hydrolysis of the carboxylic acid esters of general formula XXVI to form carboxylic acids of general formula XXVII, wherein all the groups are as hereinbefore defined, is carried out as described under Scheme 2.

The amide linking of carboxylic acids of general formula XII, wherein R¹ and R² are as hereinbefore defined and n denotes a number 1, 2, 3 or 4, and amino acids of general formula VIII, wherein R¹ and R² are as hereinbefore defined, n denotes a number 1, 2, 3 or 4 and R⁶ denotes a C₁₋₆-alkyl group, to obtain carboxylic acid amides of general formula XXVIII, wherein R¹ and R² are as hereinbefore defined, n denotes a number 1, 2, 3 or 4 and R⁶ denotes a C₁₋₆-alkyl group, is carried out as described under Scheme 1.

As mentioned under Scheme 2, the carboxylic acid ester of general formula XXVIII is cleaved to form carboxylic acid of general formula XXIX, wherein R¹ and R² are as hereinbefore defined and n denotes a number 1, 2, 3 or 4.

The amines of general formula IV used as starting materials are either commercially obtainable, or are obtained using methods known per se from the literature, for example by the methods of synthesis represented in Schemes 8 to 12, wherein R^(1.1) is as hereinbefore defined, Hal¹ denotes a chlorine or bromine atom and Hal² denotes a fluorine, chlorine or bromine atom or a group R⁹.

The reaction of an amine of general formula XXX, wherein R⁹ denotes a C₁₋₃-alkyl group, with a halo-nitrobenzene of general formula XXXI, wherein R^(1.1) is as hereinbefore defined and Hal² denotes a fluorine, chlorine or bromine atom or a group R⁹, is carried out using known methods, for example in a solvent such as tetrahydrofuran, dimethylformamide or dimethylsulphoxide and conveniently in the presence of a suitable base such as triethylamine or potassium carbonate, at a temperature of 20° C. to 160° C. If the amine of general formula XXX is liquid, the reaction may also be carried out without a solvent and additional base.

The reduction of the nitro group to form anilines of general formula XXXIII, wherein R^(1.1) is as hereinbefore defined and R⁹ denotes a C₁₋₃-alkyl group, is carried out under standard reaction conditions (see e.g. Richard C. Larock, Comprehensive Organic Transformations, 1989, VCH), preferably under standard conditions of catalytic hydrogenolysis with a catalyst such as palladium on charcoal or Raney nickel in a solvent such as methanol or ethanol.

The reaction of compounds of general formulae XXX, wherein R⁹ denotes a C₁₋₃-alkyl group, with a compound of general formula XXXIV, wherein R^(1.1) is as hereinbefore defined and Hal² denotes a fluorine, chlorine or bromine atom or a group R⁹, to obtain compounds of general formula XXXV, wherein R^(1.1) is as hereinbefore defined and R⁹ denotes a C₁₋₃-alkyl group, is carried out as described under Scheme 8.

The reduction of a nitrile of general formula XXXV to form an amine of general formula XXXVI, wherein R^(1.1) is as hereinbefore defined and R⁹ denotes a C₁₋₃-alkyl group, may be carried out under standard conditions of catalytic hydrogenolysis with a catalyst such as for example Raney nickel in a solvent such as ammoniacal methanol or ethanol or with a reducing agent such as lithium aluminium hydride or sodium borohydride in a solvent such as tetrahydrofuran, optionally in the presence of aluminium chloride.

The formylation of an amine of general formula XXXVI to obtain a compound of general formula XXXVII, wherein R^(1.1) is as hereinbefore defined and R⁹ denotes a C₁₋₃-alkyl group, is conveniently carried out in a solvent such as dichloromethane, for example at temperatures from 40° C. to 70° C. and in the presence of acetic anhydride and formic acid.

The carbamate formation to obtain compounds of general formula XXXVIII, wherein R^(1.1) is as hereinbefore defined, R⁶ denotes a C₁₋₆-alkyl and R⁹ denotes a C₁₋₃-alkyl group is carried out by known methods, for example with a chloroformic acid ester or Boc-anhydride in the presence of a base such as triethylamine or sodium hydroxide solution and a solvent such as THF or dioxane.

The reduction of the formyl or of the carbamate to obtain compounds of general formula XXXIX, wherein R^(1.1) is as hereinbefore defined and R⁹ denotes a C₁₋₃-alkyl group, is carried out under standard reaction conditions, preferably with a reducing agent such as lithium aluminium hydride and in a solvent such as tetrahydrofuran at a temperature of 50° C. to 100° C.

The halogen-nitrogen exchange in compounds of general formulae XXX, wherein R⁹ denotes a C₁₋₃-alkyl group, and XL, wherein R^(1.1) is as hereinbefore defined and Hal² denotes a fluorine, chlorine or bromine atom or a group R⁹, for preparing compounds of general formula XLI, wherein R^(1.1) is as hereinbefore defined and R⁹ denotes a C₁₋₃-alkyl group, is carried out as described under Scheme 8.

The reaction of benzaldehydes of general formula XLI, wherein R^(1.1) is as hereinbefore defined and R⁹ denotes a C₁₋₃-alkyl group, with an amine of general formula H₂NR², wherein R² is as hereinbefore defined, to obtain a compound of general formula XLII, wherein R^(1.1) and R² are as hereinbefore defined and R⁹ denotes a C₁₋₃-alkyl group, is a reductive amination. It is carried out by known methods, for example with a reducing agent such as sodium triacetoxyborohydride, sodium borohydride or sodium cyanoborohydride, conveniently in a solvent such as tetrahydrofuran or dichloromethane, optionally with the addition of acetic acid.

The reaction of an amine of general formula XXX, wherein R⁹ denotes a C₁₋₃-alkyl group, with a halogen-nitropyridine of general formula XLIII, wherein R^(1.1) is as hereinbefore defined and Hal¹ denotes a chlorine or bromine atom, is carried out by known methods, for example in a solvent such as tetrahydrofuran, dichloromethane, methanol or DMSO and conveniently in the presence of a suitable base such as triethylamine, sodium hydroxide solution or potassium carbonate and at a temperature of 20° C. to 100° C.

The subsequent reduction of the nitro group of a compound of general formula XLIV, wherein R^(1.1) is as hereinbefore defined and R⁹ denotes a C₁₋₃-alkyl group, to obtain compounds of general formula XLV, wherein R^(1.1) is as hereinbefore defined and R⁹ denotes a C₁₋₃-alkyl group, is carried out as described under Scheme 8.

The amide linking of carboxylic acids of general formula XLVI, wherein all the groups are as hereinbefore defined, and amines of general formula H₂NR², wherein R² is as hereinbefore defined, to form carboxylic acid amides of general formula XLVII, wherein all the groups are as hereinbefore defined, is carried out as described under Scheme 1.

The reduction of carboxylic acid amides of general formula XLVII to obtain amines of general formula XLVIII, wherein all the groups are as hereinbefore defined, is carried out under standard reaction conditions, preferably in the presence of a reducing agent such as lithium aluminium hydride and a solvent such as tetrahydrofuran at 40° C. to 100° C.

Description of the Method of hBK1 Receptor Binding

CHO cells expressing the hBK1 receptor are cultivated in Dulbecco's modified medium. The medium from confluent cultures is removed and the cells are washed with PBS buffer, scraped off and isolated by centrifugation. The cells are then homogenized in suspension and the homogenate is centrifuged and resuspended. The protein content is determined and the membrane preparation obtained in this manner is then frozen at −80° C.

After thawing, 200 μl of the homogenate (50 to 100 μg of proteins/assay) are incubated at room temperature with 0.5 to 1.0 nM of kallidin (DesArg10, Leu9), [3,4-prolyl-3,43H(N)] and increasing concentrations of the test substance in a total volume of 250 μl for 60 minutes. The incubation is terminated by rapid filtration through GF/B glass fibre filters which had been pretreated with polyethyleneimine (0.3%). The protein-bound radioactivity is measured in a TopCount NXT. Non-specific binding is defined as radioactivity bound in the presence of 1.0 μM of kallidin (DesArg10, Leu9), [3,4-prolyl-3,43H(N)]. The concentration/binding curve is analysed using a computer-assisted nonlinear curve fitting. The K_(i) which corresponds to the test substance is determined using the data obtained in this manner.

To demonstrate that the compounds of general formula I with different structural elements show good to very good bradykinin-B1-receptor antagonistic effects, the following Table gives the K_(i) values obtained according to the test method described above. It is pointed out that the compounds were selected for their different structural elements and not in order to emphasis specific compounds:

Example K_(i) [nM] (1) 6.2 (13) 2.1 (22) 7 (53) 2.4 (55) 0.7 (59) 6.3 (61) 3.3 (66) 4.6 (67) 0.4 (72) 2.8 (73) 6.8 (77) 8.7 (78) 5.8 (97) 6.7 (102) 5.0 (109) 6.0 (114) 4.4 (117) 0.99 (130) 5.7 (180) 5.2 (181) 7.1 (182) 4.8 (183) 6.6 (184) 1.3 (186) 3.4 (188) 9.4 (216) 4.9 (227) 4.8 (269) 7.8 (303) 6.32 (323) 2.8 (325) 0.94 (326) 6.5 (334) 8.65 (335) 9.37 (338) 1.11 (352) 9.2 (353) 6.1 (356) 8.8 (358) 3.5 (360) 4.4 (361) 7.4 (365) 2.4 (367) 2.7 (368) 1.52 (369) 3.8 (372) 2.39 (381) 8.1 (383) 6.2 (384) 9.3 (385) 6.4 (386) 6.3 (389) 3.7 (392) 8.3 (393) 1.6 (394) 1.04 (397) 7.5 (398) 0.74 (399) 3 (400) 0.79 (401) 2.7 (402) 9.3 (404) 2.8 (418) 1.2 (419) 0.65 (420) 9.1 (421) 8.7 (423) 3.4 (424) 1.4 (425) 8.3 (428) 6.3 (435) 1.5 (439) 7.5 (441) 4.6 (444) 6.9 (445) 5.6 (448) 0.82 (451) 9 (458) 4.3 (463) 2 (464) 1.5 (465) 3.8 (468) 1 (469) 8 (471) 4.1 (472) 0.68 (473) 1.8 (474) 1.4 (475) 2.4 (476) 2.35 (477) 5.8 (478) 1 (492) 3.2 (576) 0.85 (577) 0.34 (580) 6.2 (582) 9.3 (584) 9.0 (586) 5.1 (587) 9.5 (588) 1.5 (589) 5.1 (591) 1.9 (592) 2.8 (613) 9.7 (614) 2 (616) 3.7 (619) 1.2 (620) 5.9 (621) 5.8 (623) 3.4 (624) 8 (630) 5.5

Indications

By virtue of their pharmacological properties, the novel compounds and their physiologically acceptable salts are suitable for treating diseases and symptoms of diseases caused at least to some extent by stimulation of bradykinin-B1 receptors.

In view of their pharmacological effect the substances are suitable for the treatment of

(a) acute pain such as e.g. toothache, peri- and postoperative pain, traumatic pain, muscle pain, the pain caused by burns, sunburn, trigeminal neuralgia, pain caused by colic, as well as spasms of the gastro-intestinal tract or uterus; (b) visceral pain such as e.g. chronic pelvic pain, gynaecological pain, pain before and during menstruation, pain caused by pancreatitis, peptic ulcers, interstitial cystitis, renal colic, angina pectoris, pain caused by irritable bowel, non-ulcerative dyspepsia and gastritis, non-cardiac thoracic pain and pain caused by myocardial ischaemia and cardiac infarct; (c) neuropathic pain such as e.g. painful neuropathies, pain of diabetic neuropathy, AIDS-associated neuropathic pain, pain of lumbago, non-herpes-associated neuralgia, post-zoster neuralgia, nerve damage, cerebro-cranial trauma, pain of nerve damage caused by toxins or chemotherapy, phantom pain, pain of multiple sclerosis, nerve root tears and painful traumatically-caused damage to individual nerves; (d) inflammatory/pain receptor-mediated pain in connection with diseases such as osteoarthritis, rheumatoid arthritis, rheumatic fever, tendo-synovitis, tendonitis, gout, vulvodynia, damage to and diseases of the muscles and fascia (muscle injury, fibromyalgia), osteoarthritis, juvenile arthritis, spondylitis, gout-arthritis, psoriasis-arthritis, fibromyalgia, myositis, migraine, dental disease, influenza and other virus infections such as colds, systemic lupus erythematodes, (e) tumour pain associated with cancers such as lymphatid or myeloid leukaemia, Hodgkin's disease, non-Hodgkin's lymphomas, lymphogranulomatosis, lymphosarcomas, solid malignant tumours and extensive metastases; (f) headache diseases such as e.g. headache of various origins, cluster headaches, migraine (with or without aura) and tension headaches.

The compounds are also suitable for treating

(g) inflammatory changes connected with diseases of the airways such as bronchial asthma, including allergic asthma (atopic and non-atopic) as well as bronchospasm on exertion, occupationally induced asthma, viral or bacterial exacerbation of an existing asthma and other non-allergically induced asthmatic diseases; chronic obstructive pulmonary disease (COPD) including pulmonary emphysema, acute adult respiratory distress syndrome (ARDS), bronchitis, lung inflammation, allergic rhinitis (seasonal and all year round), vasomotor rhinitis and diseases caused by dust in the lungs such as aluminosis, anthracosis, asbestosis, chalicosis, siderosis, silicosis, tabacosis and byssinosis; (h) inflammatory phenomena caused by sunburn and burns, oedema after burns trauma, cerebral oedema and angiooedema, intestinal complaints including Crohn's diseases and ulcerative colitis, irritable bowel syndrome, pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis; inflammatory skin diseases (such as e.g. psoriasis and eczema), vascular diseases of the connective tissue, lupus, sprains and fractures; (i) diabetes mellitus and its effects (such as e.g. diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy) and diabetic symptoms in insulitis (e.g. hyperglycaemia, diuresis, proteinuria and increased renal excretion of nitrite and kallikrein); (j) neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease; (k) sepsis and septic shock after bacterial infections or after trauma; (l) syndromes that cause itching and allergic skin reactions; (m) osteoporosis; (n) epilepsy; (o) damage to the central nervous system; (p) wounds and tissue damage; (q) inflammation of the gums; (r) benign prostatic hyperplasia and hyperactive bladder; (s) pruritus; (t) vitiligo; (u) disorders of the motility of respiratory, genito-urinary, gastro-intestinal or vascular regions and (v) post-operative fever.

In addition to being suitable as human therapeutic agents, these substances are also useful in the veterinary treatment of domestic animals, exotic animals and farm animals.

For treating pain, it may be advantageous to combine the compounds according to the invention with stimulating substances such as caffeine or other pain-alleviating active compounds. If active compounds suitable for treating the cause of the pain are available, these can be combined with the compounds according to the invention. If, independently of the pain treatment, other medical treatments are also indicated, for example for high blood pressure or diabetes, the active compounds required can be combined with the compounds according to the invention.

The following compounds may be used for combination therapy, for example:

Non-steroidal antirheumatics (NSAR): COX-2 inhibitors such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenhufen, fenoprofen, fiuprofen, fiulbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alcofenac, isoxepac, oxpinax, sulindac, tiopinac, tolmetin, zidometacin, zomepirac) fenamic derivatives (meclofenamic acid, mefenamic acid, tolfenamic acid), biphenyl-carboxylic acid derivatives, oxicams (isoxicam, meloxicam, piroxicam, sudoxicam and tenoxicam), salicylic acid derivatives (acetylsalicylic acid, sulphasalazin, why not also mesalazin, olsalazin, and pyrazolone (apazone, bezpiperylone, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone, why not also propyphenazone and metamizol, and coxibs (celecoxib, valecoxib, rofecoxib, etoricoxib).

Opiate receptor agonists such as e.g. morphine, propoxyphen (Darvon), tramadol, buprenorphine.

Cannabinoid agonists such as e.g. GW-1000, KDS-2000, SAB-378, SP-104, NVP001-GW-843166, GW-842166X, PRS-211375.

Sodium channel blockers such as e.g. carbamazepine, mexiletin, lamotrigin, pregabalin, tectin, NW-1029, CGX-1002.

N-type calcium channel blockers such as e.g. ziconitide, NMED-160, SP1-860.

Serotonergic and noradrenergic modulators such as e.g. SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram.

Corticosteroids such as e.g. betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone.

Histamine H1-receptor antagonists such as e.g. bromopheniramine, chloropheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine azatadine, cyproheptadine, antazoline, pheniramine, pyrilamine, astemizole, terfenadine, loratadine, cetirizine, desloratadine, fexofenadine, levocetirizine.

Histamine H2-receptor antagonists such as e.g. cimetidine, famotidine, and ranitidine.

Proton pump inhibitors such as e.g. omeprazole, pantoprazole, esomeprazole.

Leukotriene antagonists and 5-lipoxygenasehemmer such as e.g. zafirlukast, montelukast, pranlukast and zileuton.

Local anaesthetics such as e.g. ambroxol, lidocaine.

VR1 agonists and antagonists such as e.g. NGX-4010, WL-1002, ALGRX-4975, WL-10001, AMG-517.

Nicotine receptor agonists such as e.g. ABT-202, A-366833, ABT-594, BTG-102, A-85380, CGX1204.

P2X3-receptor antagonists such as e.g. A-317491, ISIS-13920, AZD-9056.

NGF agonists and antagonists such as e.g. RI-724, RI-1024, AMG-819, AMG-403, PPH 207.

NK1 and NK2 antagonists such as e.g. DA-5018, R-116301, CP-728663, ZD-2249.

NMDA antagonists such as e.g. NER-MD-11, CNS-5161, EAA-090, AZ-756, CNP-3381.

potassium channel modulators such as e.g. CL-888, ICA-69673, retigabin.

GABA modulators such as e.g. lacosamide.

Serotonergic and noradrenergic modulators such as e.g. SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram, flibanserine.

Anti-migraine drugs such as e.g. sumatriptan, zolmitriptan, naratriptan, eletriptan.

The dosage necessary for obtaining a pain-alleviating effect is, in the case of intravenous administration, expediently from 0.01 to 3 mg/kg of body weight, preferably from 0.1 to 1 mg/kg, and, in the case of oral administration, from 0.1 to 8 mg/kg of body weight, preferably from 0.5 to 3 mg/kg, in each case 1 to 3 times per day. The compounds prepared according to the invention can be administered intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, aerosol formulations being particularly suitable for inhalation. They can be incorporated into customary pharmaceutical preparations, such as tablets, coated tablets, capsules, powders, suspensions, solutions, metered-dose aerosols or suppositories, if appropriate together with one or more customary inert carriers and/or diluents, for example with maize starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances, such as hardened fat, or suitable mixtures thereof.

Experimental Section

Generally, there are IR, ¹H NMR and/or mass spectra for the compounds that were prepared. The ratios given for the eluants are in volume units of the solvents in question. For ammonia, the given volume units are based on a concentrated solution of ammonia in water.

Unless indicated otherwise, the acid, base and salt solutions used for working up the reaction solutions are aqueous systems having the stated concentrations.

For chromatographic purification, silica gel from Millipore (MATREX™, 35-70 μm) or Alox (E. Merck, Darmstadt, Alumina 90 standardized, 63-200 μm, article No. 1.01097.9050) are used.

In the descriptions of the experiments, the following abbreviations are used:

-   CDI 1,1′-carbonyldiimidazole -   TLC thin layer chromatogram -   DIPEA diisopropylethylamine -   DMAP 4-dimethylaminopyridine -   DMF dimethylformamide -   DMSO dimethylsulphoxide -   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium     hexafluorophosphate -   tert tertiary -   TBTU     2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate -   THF tetrahydrofuran

The following analytical HPLC methods were used:

Method 1: column: XTerra ™ MS C18, 2.5 μM, 4.6 × 30 mm detection: 210-420 nm eluant A: water/0.1% formic acid eluant B: acetonitrile/0.1% formic acid time in min % A % B flow rate in mL/min gradient: 0.0 95.0  5.0 1.0 0.1 95.0  5.0 1.0 3.1  2.0 98.0 1.0 4.5  2.0 98.0 1.0 5.0 95.0  5.0 1.0

Method 2: column: Microsorb C18, 3 μM, 4.6 × 50 mm detection: 220-320 nm eluant A: water/0.1% TFA eluant B: acetonitrile/0.1% TFA time in min % A % B flow rate in mL/min gradient: 0.0 95.0  5.0 1.5 0.5 95.0  5.0 1.5 3.8  2.0 98.0 1.5 4.3  2.0 98.0 1.5 4.35 95.0  5.0 1.5 4.6 95.0  5.0 1.5

Method 3: column: XTerra ™ MS C18, 3.5 μM, 4.6 × 50 mm detection: 210-420 nm eluant A: water/0.1% formic acid eluant B: acetonitrile/0.1% formic acid time in min % A % B flow rate in mL/min gradient: 0.0 95.0  5.0 1.0 0.1 95.0  5.0 1.0 7.1  2.0 98.0 1.0 7.9  2.0 98.0 1.0 8.0 95.0  5.0 1.0

Method 4: column: Zorbax Stable Bond C18, 3.5 μM, 4.6 × 75 mm detection: 230-360 nm eluant A: water/0.1% formic acid eluant B: acetonitrile/0.1% formic acid time in flow rate min % A % B in mL/min gradient: 0.0 95.0  5.0 1.6 0.1 95.0  5.0 1.6 4.5 10.0 90.0 1.6 5.09 10.0 90.0 1.6 5.5 90.0 10.0 1.6

Method 5: column: Interchim Strategy C18, 5 μM, 4.6 × 50 mm detection: 220-320 nm eluant A: water/0.1% TFA eluant B: acetonitrile time in flow rate min % A % B in mL/min gradient: 0.0 95.0  5.0 3.0 0.3 95.0  5.0 3.0 2.0  2.0 98.0 3.0 2.4  2.0 98.0 3.0 2.45 95.0  5.0 3.0 2.8 95.0  5.0 3.0

Method column: Merck Cromolith Speed ROD RP18e, 4.6 × 50 mm 6: detection: 190-400 nm eluant A: water/0.1% formic acid eluant B: acetonitrile/0.1% formic acid time in flow rate min % A % B in mL/min gradient: 0.0 90.0 10.0 1.5 4.5 10.0 90.0 1.5 5.0 10.0 90.0 1.5 5.5 90.0 10.0 1.5

Method 7: column: Waters SunFire C18, 3.5 μM, 4.6 × 50 mm detection: 210-500 nm eluant A: water/0.1% TFA eluant B: acetonitrile/0.1% TFA time in flow rate min % A % B in mL/min gradient: 0.0 95.0  5.0 1.5 2.0  2.0 98.0 1.5 3.0  2.0 98.0 1.5 3.4 95.0  5.0 1.5

Method 8: column: Waters XBridge C18, 3.5 μM, 4.6 × 50 mm detection: 210-500 nm eluant A: water/0.1% TFA eluant B: acetonitrile/0.1% TFA time in flow rate min % A % B in mL/min gradient: 0.0 95.0  5.0 1.0 0.1 95.0  5.0 1.0 5.1  2.0 98.0 1.0 6.5  2.0 98.0 1.0 7.0 95.0  5.0 1.0

Method 9: column: Merck Chromolith ™ Flash RP18e, 4.6 × 25 mm detection: 190-400 nm eluant A: water/0.1% formic acid eluant B: acetonitrile/0.1% formic acid time in flow rate min % A % B in mL/min gradient: 0.0 90.0 10.0 1.6 2.7 10.0 90.0 1.6 3.0 10.0 90.0 1.6 3.3 90.0 10.0 1.6

Method column: Merck Chromolith ™ Flash RP18e, 4.6 × 25 mm 10: detection: 210-400 nm eluant A: water/0.1% TFA eluant B: acetonitrile/0.1% TFA time in flow rate min % A % B in mL/min gradient: 0.0 95.0  5.0 2.5 0.2 95.0  5.0 2.5 1.5  2.0 98.0 2.5 1.7  2.0 98.0 2.5 1.9 95.0  5.0 2.5 2.2 95.0  5.0 2.5

Method 11: column: Waters XBridge C18, 3.5 μM, 4.6 × 50 mm detection: 210-500 nm eluant A: water/0.1% TFA eluant B: acetonitrile/0.1% TFA time in flow rate min % A % B in mL/min gradient: 0.0 95.0  5.0 1.5 2.0  0.0 100.0 1.5 3.0  0.0 100.0 1.5 3.4 95.0  5.0 1.5

Method 12: column: YMC-Pack ODS-AQ, 3.0 μM, 4.6 × 75 mm detection: 230-360 nm eluant A: water/0.1% formic acid eluant B: acetonitrile/0.1% formic acid time in flow rate min % A % B in mL/min gradient: 0.0 95.0  5.0 1.6 4.5 10.0 90.0 1.6 5.0 10.0 90.0 1.6 5.5 90.0 10.0 1.6

The following microwave apparatus was used: Biotage EmrysOptimizer™

Preparation of the End Compounds EXAMPLE 1

1a)

A mixture of 1.0 g (4.07 mmol) of 2,3-dichlorobenzenesulphonic acid chloride, 0.33 g (4.89 mmol) of methylamine hydrochloride, 2.73 ml (19.55 mmol) of triethylamine and 20 ml dichloromethane is stirred overnight at ambient temperature. The reaction mixture is then washed once with 1N HCl, saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried on sodium sulphate and then evaporated to dryness.

C₇H₇Cl₂NO₂S (240.11)

[M+H]+=240/242/244

TLC: silica gel, petroleum ether/ethyl acetate 2:1, Rf value=0.50

1b)

A mixture of 0.9 g (3.75 mmol) of product from 1a and 20 ml DMF is taken and combined with 1.55 g (11.24 mmol) of potassium carbonate and 0.49 ml (4.50 mmol) of ethyl 3-bromopropionate. The reaction mixture is stirred overnight at ambient temperature and then mixed with water. It is extracted twice with ethyl acetate. The organic extracts are washed three times with water and once with saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness.

C₁₁H₁₃Cl₂NO₄S (326.20)

[M+H]+=326/328/330

TLC: silica gel, petroleum ether/ethyl acetate 2:1, Rf value=0.45

1c)

A mixture of 1.15 g (3.53 mmol) of product from 1b, 0.74 g (17.63 mmol) of lithium hydroxide monohydrate, 15 ml THF and 15 ml of water is stirred for one hour at ambient temperature. Then the THF is eliminated in vacuo and the residue is acidified with concentrated HCl. The reaction mixture is then extracted three times with ethyl acetate. The organic extracts are washed with saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness. The crude product is triturated with diethyl ether and suction filtered.

C₁₀H₁₁Cl₂NO₄S (312.17)

[M+H]+=310/312/314

TLC: silica gel, petroleum ether/ethyl acetate 2:1, Rf value=0.03

1d)

A mixture of 5.0 g (30.63 mmol) of 1-pyridin-4-yl-piperazine, 4.32 g (30.63 mmol) of 1-fluoro-4-nitrobenzene (Aldrich), 10.62 ml (76.59 mmol) of triethylamine and 100 ml DMF is heated for 50 min at reflux temperature and then evaporated to dryness. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/ethanol/ammonia 12:1:0.1 to 10:1:0.1).

C₁₅H₁₆N₄O₂ (284.31)

[M+H]+=285

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.52

1e)

A mixture of 4.95 g (17.41 mmol) of product from 1d, 0.6 g palladium on charcoal (10%), 120 ml dichloromethane and 20 ml of methanol is hydrogenated for five hours in the autoclave at ambient temperature. Then the mixture is suction filtered and the filter cake is decocted another six times with dichloromethane/methanol 1:1 and suction filtered again. The combined filtrates are evaporated to dryness in vacuo.

C₁₅H₁₈N₄ (254.33)

[M+H]+=255

1f)

A mixture of 1.25 g (4.00 mmol) of product from 1c, 2.0 ml (14.34 mmol) of triethylamine, 1.28 g (4.00 mmol) of TBTU and 7 ml DMF is stirred for 45 min at ambient temperature. Then 1.0 g (3.93 mmol) of product from 1e is added and the mixture is stirred overnight at ambient temperature. Then the reaction mixture is poured into water and extracted with dichloromethane. The organic extracts are washed with water, dried on Na₂SO₄ and evaporated to dryness. The crude product thus obtained was purified by column chromatography through silica gel (eluant: dichloromethane with 5-20% methanol).

C₂₅H₂₇Cl₂N₅O₃S (548.49)

[M+H]+=548/550/552

TLC: silica gel, dichloromethane/methanol 4:1, Rf value=0.65

EXAMPLE 2

2a)

A mixture of 0.5 g (2.17 mmol) of N-(1-benzylpiperidin-4-yl)-phthalimide (Bioorg. Med. Chem. Lett. 11, 2001, 2325-2330), 0.33 g (2.17 mmol) of 4-chloropyridine hydrochloride, 1.2 ml (8.69 mmol) of triethylamine and 2.4 ml of absolute ethanol is heated in the microwave to 150° C. for one hour. The reaction mixture is then diluted with ethanol, the precipitate formed is filtered off. The filtrates are evaporated to dryness and the crude product is purified by preparative HPLC.

C₁₈H₁₇N₃O₂×C₂HF₃O₂ (421.37)

[M+H]+=308

HPLC (Method 1): retention time=2.07 min

2b)

A mixture of 0.3 g (0.71 mmol) of product from 2a, 0.09 g (1.42 mmol) of hydrazine hydrate 80% and 6 ml of absolute ethanol is refluxed for four hours. The reaction mixture is then cooled to 0° C., the precipitate formed is filtered off. The filtrates are evaporated to dryness.

C₁₀H₁₅N₃ (177.25)

[M+H]+=178

2c)

Example 2 is prepared analogously to 1f from 0.22 g (0.71 mmol) of product from 1c, 0.24 g (1.35 mmol) of product from 2b, 0.3 ml (2.13 mmol) of triethylamine and 0.23 g (0.71 mmol) of TBTU in 5.5 ml DMF.

C₂₀H₂₄Cl₂N₄O₃S (471.40)

[M+H]+=471/473/475

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.2

EXAMPLE 3

3a)

A mixture of 0.99 g (4.00 mmol) of 4-methoxy-2,3,6-trimethyl-benzenesulphonyl chloride, 0.69 g (4.51 mmol) of β-alanine ethylester hydrochloride, 2.23 ml (15.98 mmol) of triethylamine and 20 ml dichloromethane is stirred overnight at ambient temperature. The reaction mixture is then washed with 0.5 M HCl, saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₅H₂₃NO₅S (329.41)

[M+H]+=330

TLC: silica gel, petroleum ether/ethyl acetate 2:1, Rf value=0.43

3b)

A mixture of 1.24 g (3.76 mmol) of product from 3a, 0.84 ml (13.55 mmol) of methyl iodide, 1.04 g (7.53 mmol) of anhydrous potassium carbonate and 10 ml DMF is stirred for five hours at ambient temperature. The reaction mixture is then evaporated to dryness in vacuo, the residue is taken up in ethyl acetate. It is washed with water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₆H₂₅NO₅S (343.44)

[M+H]+=344

TLC: silica gel, petroleum ether/ethyl acetate 2:1, Rf value=0.52

3c)

The acid is prepared analogously to 1c from 1.29 g (3.76 mmol) of product from 3b, 0.79 g (18.80 mmol) of lithium hydroxide monohydrate, 15 ml THF and 15 ml of water.

C₁₄H₂₁NO₅S (315.39)

[M+H]+=316

TLC: silica gel, petroleum ether/ethyl acetate 2:1, Rf value=0.07

3d)

Example 3 is prepared analogously to 1f from 0.15 g (0.47 mmol) of product from 3c, 0.12 g (0.47 mmol) of product from 1e, 0.2 ml (1.43 mmol) of triethylamine and 0.15 g (0.48 mmol) of TBTU in 8 ml DMF.

C₂₉H₃₇N₅O₄S (551.70)

[M+H]+=552

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.38

EXAMPLE 4

Example 4 is prepared analogously to 1f from 0.39 g (1.26 mmol) of product from 1c, 0.24 g (1.26 mmol) of 4-(4-methylpiperazin-1-yl)-aniline (J. Med. Chem. SIR 48, 7, 2005, 2371-2387), 0.35 ml (2.51 mmol) of triethylamine and 0.50 g (1.32 mmol) of HATU in 5 ml DMF.

C₂₁H₂₆CL₂N₄O₃S (485.43)

[M+H]+=485/487/489

HPLC (Method 2): retention time=2.64 min

EXAMPLE 5

5a)

5a is prepared analogously to 1f from 0.39 g (1.26 mmol) of product from 1c, 0.24 g (1.26 mmol) of 4-(4-methylpiperazin-1-yl)-aniline (J. Med. Chem. SIR 48, 7, 2005, 2371-2387), 0.35 ml (2.51 mmol) of triethylamine and 0.50 g (1.32 mmol) of HATU in 5 ml DMF.

C₂₅H₃₂CL₂N₄O₅S (571.52)

5b)

A mixture of 0.60 g (1.05 mmol) of product from 5a, 3 ml TFA and 3 ml dichloromethane is stirred for two hours at ambient temperature. The reaction mixture is evaporated to dryness and the crude product is purified by preparative HPLC.

C₂₀H₂₄Cl₂N₄O₃S (471.40)

[M+H]+=471/473/475

HPLC (Method 2): retention time=2.58 min

EXAMPLE 6

Example 6 is prepared analogously to 1f from 0.22 g (0.71 mmol) of product from 1c, 0.12 g (0.78 mmol) of 3-(4-methylpiperazin-1-yl)-propylamine (Bioorg. Med. Chem. Lett. 13, 2003, 2131-2136), 0.30 ml (2.13 mmol) of triethylamine and 0.23 g (0.71 mmol) of TBTU in 5.5 ml THF.

C₁₈H₂₈Cl₂N₄O₃S×2C₂HF₃O₂ (679.46)

[M+H]+=451/453/455

HPLC (Method 5): retention time=1.37 min

EXAMPLE 7

Example 7 is prepared analogously to 1f from 0.22 g (0.71 mmol) of product from 1c, 0.14 g (0.71 mmol) of 4-(1-methylpiperidin-4-yl)-aniline (JW Pharmlab), 0.30 ml (2.13 mmol) of triethylamine and 0.23 g (0.71 mmol) of TBTU in 5.5 ml THF.

C₂₂H₂₇Cl₂N₃O₃S×C₂HF₃O₂ (598.46)

[M+H]+=484/486/488

HPLC (Method 5): retention time=1.57 min

EXAMPLE 8

8a)

8a is prepared analogously to 1d from 0.5 g (3.90 mmol) of 4-dimethylamino-piperidine (Alfa Aesar), 0.44 g (4.18 mmol) of 1-fluoro-4-nitrobenzene (Aldrich) and 1.33 ml (76.59 mmol) of triethylamine in 12 ml DMF.

C₁₃H₁₉N₃O₂ (249.31)

[M+H]+=250

8b)

A mixture of 1.66 g (6.67 mmol) of product from 8a, 0.17 g palladium on charcoal (5%) and 132 ml of ethanol is hydrogenated in the autoclave at ambient temperature. Then the catalyst is removed by suction filtering and the filtrate is evaporated to dryness in vacuo.

C₁₃H₂₁N₃ (219.33)

[M+H]+=220

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.1

8c)

Example 8 is prepared analogously to 1f from 0.22 g (0.71 mmol) of product from 1c, 0.16 g (0.71 mmol) of product from 8b, 0.30 ml (2.13 mmol) of triethylamine and 0.23 g (0.71 mmol) of TBTU in 5.5 ml THF.

C₂₃H₃₀Cl₂N₄O₃S×2C₂HF₃O₂ (741.53)

[M+H]+=513/515/517

HPLC (Method 5): retention time=1.46 min

EXAMPLE 9

9a)

13 ml acetic anhydride are taken and 8 ml formic acid are slowly added thereto. The reaction mixture is heated for 1.5 hours to 50° C. and then combined with 80 ml dichloromethane. While cooling with the ice bath 5.0 g (19.66 mmol) are then added. The mixture is stirred for one hour at ambient temperature and then evaporated to dryness. The residue is combined with semisaturated sodium hydrogen carbonate solution and extracted twice with dichloromethane. The organic extracts are washed with saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol/ammonia 9:1:0.1).

C₁₆H₁₈N₄O (282.34)

[M+H]+=283

9b)

At 60° C. a mixture of 10.63 ml lithium aluminium hydride 2 M in THF (21.25 mmol) and 50 ml THF is slowly combined with 3.0 g (10.63 mmol) of product from 9a. The reaction mixture is stirred for eight hours at 60° C. and four hours at ambient temperature. While cooling with the ice bath 20 ml of water are then added. The mixture is filtered through Celite and washed with THF and dichloromethane. The filtrate is evaporated to dryness. The residue is combined with dichloromethane, washed with water and 1 M sodium hydroxide solution, dried on sodium sulphate solution and evaporated to dryness. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol/ammonia 9:1:0.1).

C₁₆H₂₀N₄ (268.36)

9c)

Example 9 is prepared analogously to 1f from 0.15 g (0.48 mmol) of product from 1c, 0.14 g (0.51 mmol) of product from 9b, 0.13 ml (0.96 mmol) of triethylamine and 0.19 g (0.51 mmol) of HATU in 5 ml DMF.

C₂₆H₂₉Cl₂N₅O₃S (562.51)

[M+H]+=562/564/566

HPLC (Method 2): retention time=2.86 min

EXAMPLE 10

10a)

A mixture of 1.0 g (9.70 mmol) of N-methyl-β-alanine (Convertex), 24 ml dioxane, 12 ml of water and 2.68 g (19.38 mmol) of anhydrous potassium carbonate is combined with 2.33 g (10.66 mmol) of Boc-anhydride while cooling with an ice bath. The reaction mixture is stirred for three days at ambient temperature. Then the dioxane is eliminated in vacuo. The aqueous residue is extracted with ethyl acetate (ethyl acetate phases are discarded), then acidified slightly with 1 M hydrochloric acid and then extracted with dichloromethane. The organic dichloromethane extracts are washed with saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness.

C₉H₁₇NO₄ (203.24)

[M+H]+=204

10b)

10b is prepared analogously to 1f from 1.85 g (9.10 mmol) of product from 10a, 2.32 g (9.10 mmol) of product from 1e, 3.81 ml (27.31 mmol) of triethylamine and 2.92 g (9.10 mmol) of TBTU in 80 ml DMF.

C₂₄H₃₃N₅O₃ (439.55)

[M+H]+=440

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.49

10c)

A mixture of 3.20 g (7.28 mmol) of product from 10b, 20 ml TFA and 60 ml dichloromethane is stirred for 30 min at ambient temperature. Then the reaction mixture is evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/ethanol/ammonia 9:1:0.1 to 4:1:0.1).

C₁₉H₂₅N₅O (339.43)

[M+H]+=340

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.25

10d)

A mixture of 0.1 g (0.30 mmol) of product from 10c, 0.056 g (0.25 mmol) of 1-naphthylsulphonic acid chloride, 0.137 ml (0.98 mmol) of triethylamine and 5 ml dichloromethane is stirred overnight at ambient temperature. Then the reaction mixture is evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/ethanol/ammonia 12:1:0.1).

C₂₉H₃₁N₅O₃S (529.65)

[M+H]+=530

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.44

EXAMPLE 11

Example 11 is prepared analogously to 10d from 0.10 g (0.30 mmol) of product from 10c, 0.052 g (0.25 mmol) of 2-chlorobenzenesulphonic acid chloride, 0.14 ml (98 mmol) of triethylamine in 5 ml dichloromethane.

C₂₅H₂₈ClN₅O₃S (514.04)

[M+H]+=514/516

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.47

EXAMPLE 12

Example 12 is prepared analogously to 10d from 0.10 g (0.30 mmol) of product from 10c, 0.047 g (0.25 mmol) of p-toluenesulphonic acid chloride, 0.14 ml (98 mmol) of triethylamine in 5 ml dichloromethane.

C₂₆H₃₁N₅O₃S (493.62)

[M+H]+=494

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.43

EXAMPLE 13

13a)

A mixture of 2.0 g (14.69 mmol) of 3,5-dimethylanisol and 20 ml dichloromethane is combined with 5.85 ml (88.0 mmol) of chlorosulphonic acid while cooling with an ice bath. The reaction mixture is then stirred for 20 min at ambient temperature and then poured onto 50 ml ice water. The mixture is extracted with 100 ml dichloromethane. The organic extracts are washed with 5% sodium hydrogen carbonate solution, dried on sodium sulphate and evaporated to dryness.

C₉H₁₁ClO₃S (234.70)

[M+H]+=234/236

TLC: silica gel, petroleum ether/ethyl acetate 9:1, Rf value=0.46

13b)

Example 13 is prepared analogously to 10d from 0.10 g (0.30 mmol) of product from 10c, 0.058 g (0.25 mmol) of product from 13a, 0.14 ml (98 mmol) of triethylamine in 5 ml dichloromethane.

C₂₈H₃₅N₅O₄S (537.67)

[M+H]+=538

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.62

EXAMPLE 14

Example 14 is prepared analogously to 10d from 0.10 g (0.30 mmol) of product from 10c, 0.047 g (0.25 mmol) of m-toluenesulphonic acid chloride, 0.14 ml (98 mmol) of triethylamine in 5 ml dichloromethane.

C₂₆H₃₁N₅O₃S (493.62)

[M+H]+=494

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.47

EXAMPLE 15

Example 15 is prepared analogously to 10d from 0.10 g (0.30 mmol) of product from 10c, 0.047 g (0.25 mmol) of o-toluenesulphonic acid chloride, 0.14 ml (98 mmol) of triethylamine in 5 ml dichloromethane.

C₂₆H₃₁N₅O₃S (493.62)

[M+H]+=494

HPLC (Method 1): retention time=2.37 min

EXAMPLE 16

Example 16 is prepared analogously to 10d from 0.10 g (0.30 mmol) of product from 10c, 0.043 g (0.25 mmol) of benzenesulphonic acid chloride, 0.14 ml (98 mmol) of triethylamine in 5 ml dichloromethane.

C₂₅H₂₉N₅O₃S (479.60)

[M+H]+=480

HPLC (Method 1): retention time=2.40 min

EXAMPLE 17

17a)

A mixture of 1.03 g (6.28 mmol) of 1-(4-pyridyl)-piperazine (Girindus) and 50 ml dichloromethane is combined with 1.0 g (6.28 mmol) of tert-butyl-N-(2-oxoethyl)-carbamate (Aldrich). The reaction mixture is then stirred for 30 min at ambient temperature, then combined with 2.66 g (12.56 mmol) of sodium-triacetoxyborohydride while cooling with an ice bath and then stirred overnight at ambient temperature. Another 60 ml dichloromethane are added and the reaction mixture is washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. The organic phase is dried on sodium sulphate and evaporated to dryness. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/ethanol/ammonia 14:1:0.1 to 10:1:0.1).

C₁₆H₂₆N₄O₂ (306.40)

[M+H]+=307

17b)

A mixture of 0.36 g (1.19 mmol) of product from 17a, 1.19 ml (15.50 mmol) of TFA and 2 ml dichloromethane is stirred for two hours at ambient temperature. Then the reaction mixture is evaporated to dryness in vacuo.

C₁₁H₁₈N₄×2C₂HF₃O₂ (434.33)

[M+H]+=207

HPLC (Method 2): retention time=0.98 min

17c)

Example 17 is prepared analogously to 1f from 0.22 g (0.71 mmol) of product from 1c, 0.34 g (0.78 mmol) of product from 17b, 0.50 ml (3.56 mmol) of triethylamine and 0.23 g (0.71 mmol) of TBTU in 5.5 ml THF.

C₂₁H₂₇Cl₂N₅O₃S×2C₂HF₃O₂ (728.49)

[M+H]+=500/502/504

HPLC (Method 2): retention time=3.14 min

EXAMPLE 18

17a)

18a is prepared analogously to 1f from 0.20 g (0.64 mmol) of product from 1c, 0.17 g (0.64 mmol) of tert-butyl 4-(4-aminobutyl)-piperazine-1-carboxylate (J. Med. Chem. 47, 2004, 4300-4315), 0.27 ml (1.92 mmol) of triethylamine and 0.21 g (0.64 mmol) of TBTU in 5 ml THF.

C₂₃H₃₆CL₂N₄O₅S (551.53)

M+H]+=551/553/555

TLC: silica gel, dichloromethane/methanol 30:1, Rf value=0.1

18b)

A mixture of 0.29 g (0.53 mmol) of product from 18a, 0.53 ml TFA and 1 ml dichloromethane is stirred for two hours at ambient temperature. The reaction mixture is washed with saturated sodium hydrogen carbonate solution. After the phase separation the aqueous phase is extracted three times more with dichloromethane. The organic extracts are dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₈H₂₈Cl₂N₄O₃S (451.41)

[M+H]+=451/453/455

HPLC (Method 2): retention time=2.22 min

EXAMPLE 19

19a)

A mixture of 5.0 ml (45.13 mmol) of N-methylpiperazine and 0.73 g (6.00 mmol) of 4-fluorobenzonitrile (Aldrich) is heated for 12 hours to 80° C. Then it is evaporated to dryness and the residue is mixed with water. It is extracted three times with ethyl acetate. The organic extracts are dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₂H₁₅N₃ (201.27)

M+H]+=202

TLC: silica gel, dichloromethane/ethanol 95:5, Rf value=0.31

19b)

A mixture of 1.17 g (5.81 mmol) of product from 19a, 0.3 g Raney nickel and 50 ml of methanolic ammonia solution is hydrogenated at 50° C. in the autoclave. Then the catalyst is filtered off and the filtrate is evaporated to dryness in vacuo.

C₁₂H₁₉N₃ (205.30)

M+H]+=206

19c)

Example 19 is prepared analogously to 1f from 0.16 g (0.50 mmol) of product from 1c, 0.10 g (0.50 mmol) of product from 19b, 0.14 ml (1.00 mmol) of triethylamine and 0.16 g (0.50 mmol) of TBTU in 3 ml DMF.

C₂₂H₂₈Cl₂N₄O₃S×HCl (535.91)

[M+H]+=499/501/503

HPLC (Method 3): retention time=3.49 min

EXAMPLE 20

20a)

A mixture of 0.5 g (4.99 mmol) of N-methylpiperazine (Aldrich), 1.41 g (4.99 mmol) of N-(4-bromobutyl)-phthalimide (Fluka), 0.86 ml (4.99 mmol) of DIPEA and 9.3 ml acetonitrile is heated for 45 min in the microwave to 120° C. Then it is evaporated to dryness. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol 98:2).

C₁₇H₂₃N₃O₂ (301.38)

M+H]+=302

20b)

A mixture of 1.94 g (6.44 mmol) of product from 20a, 1.61 g (25.75 mmol) of hydrazine hydrate and 15 ml of absolute ethanol is heated for 5.5 hours in the autoclave to 120° C. The precipitate formed is filtered off. Then the filtrate is evaporated to dryness.

C₉H₂₁N₃ (171.28)

20c)

Example 20 is prepared analogously to 1f from 0.50 g (1.61 mmol) of product from 1c, 0.55 g (3.22 mmol) of product from 20b, 0.67 ml (4.83 mmol) of triethylamine and 0.52 g (1.61 mmol) of TBTU in 30 ml DMF.

C₁₉H₃₀Cl₂N₄O₃S×2HCl (538.36)

[M+H]+=465/467/469

HPLC (Method 1): retention time=2.15 min

EXAMPLE 21

21a)

A mixture of 2.06 g (12.62 mmol) of 1-pyridin-4-yl-piperazine (Girindus), 2.00 g (12.62 mmol) of 2-chloro-5-nitropyridine (Fluka) and 50 ml dichloromethane is stirred for 15 min at ambient temperature and then combined with 6.31 ml (12.62 mmol) of 2 M sodium hydroxide solution. The reaction mixture is stirred for 20 hours at ambient temperature and then combined with 300 ml dichloromethane and 100 ml 5% sodium hydrogen carbonate solution. After the phase separation the organic phase is dried on sodium sulphate and evaporated to dryness in vacuo. The crude product is stirred with 100 ml diethyl ether/ethanol 2:1, filtered off and dried.

C₁₄H₁₅N₅O₂ (285.30)

[M+H]+=286

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.10

21b)

A mixture of 1.75 g (6.13 mmol) of product from 21a, 0.4 g palladium on charcoal (10%), 100 ml dichloromethane and 50 ml of methanol is hydrogenated for five hours in the autoclave at ambient temperature. Then the catalyst is removed by suction filtering and the filtrate is evaporated to dryness in vacuo. The residue is stirred with 100 ml diethyl ether/ethanol 2:1 and suction filtered. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol/ammonia 95:5:0.5).

C₁₄H₁₇N₅ (255.32)

[M+H]+=256

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.37

21c)

Example 21 is prepared analogously to 1f from 0.11 g (0.35 mmol) of product from 1c, 0.089 g (0.35 mmol) of product from 21b, 0.098 ml (0.70 mmol) of triethylamine and 0.13 g (0.42 mmol) of TBTU in 15 ml THF.

C₂₄H₂₆Cl₂N₆O₃S (549.47)

[M+H]+=549/551/553

HPLC (Method 4): retention time=2.7 min

EXAMPLE 22

22a)

22a is prepared analogously to 3a from 3.00 g (12.78 mmol) of product from 13a, 2.16 g (14.06 mmol) of β-alanine ethylester hydrochloride, 7.13 ml (51.13 mmol) of triethylamine in 70 ml dichloromethane.

C₁₄H₂₁NO₅S (315.39)

[M+H]+=316

TLC: silica gel, petroleum ether/ethyl acetate 2:1, Rf value=0.23

22b)

22b is prepared analogously to 3b from 4.06 g (12.87 mmol) of product from 22a, 2.40 ml (38.62 mmol) of methyl iodide, 3.56 g (25.75 mmol) of potassium carbonate anhydrous in 40 ml DMF.

C₁₅H₂₃NO₅S (329.41)

[M+H]+=330

TLC: silica gel, petroleum ether/ethyl acetate 2:1, Rf value=0.36

22c)

The acid is prepared analogously to 1c from 3.83 g (11.63 mmol) of product from 22b, 2.44 g (58.13 mmol) of lithium hydroxide monohydrate in 30 ml THF and 30 ml of water.

C₁₃H₁₉NO₅S (301.36)

[M+H]+=302

TLC: silica gel, petroleum ether/ethyl acetate 1:1, Rf value=0.12

22d)

Example 22 is prepared analogously to 1f from 0.13 g (0.42 mmol) of product from 22c, 0.089 g (0.35 mmol) of product from 21b, 0.098 ml (0.70 mmol) of triethylamine and 0.13 g (0.42 mmol) of TBTU in 15 ml THF.

C₂₇H₃₄N₆O₄S (538.66)

[M+H]+=539

HPLC (Method 4): retention time=2.6 min

EXAMPLE 23

Example 23 is prepared analogously to 1f from 0.30 g (1.00 mmol) of product from 22c, 0.22 g (1.00 mmol) of product from 8b, 0.42 ml (2.99 mmol) of triethylamine and 0.32 g (1.00 mmol) of TBTU in 15 ml DMF.

C₂₆H₃₈N₄O₄S (502.67)

[M+H]+=503

HPLC (Method 1): retention time=2.47 min

EXAMPLE 24

Example 24 is prepared analogously to 1f from 0.25 g (0.80 mmol) of product from 3c, 0.18 g (0.80 mmol) of product from 8b, 0.33 ml (2.39 mmol) of triethylamine and 0.26 g (0.80 mmol) of TBTU in 10 ml DMF.

C₂₇H₄₀N₄O₄S (516.70)

[M+H]+=517

HPLC (Method 1): retention time=2.50 min

EXAMPLE 25

Example 25 is prepared analogously to 1f from 0.20 g (0.66 mmol) of product from 22c, 0.14 g (0.73 mmol) of 4-(1-methylpiperidin-4-yl)-aniline (JW Pharmlab), 0.28 ml (1.99 mmol) of triethylamine and 0.21 g (0.66 mmol) of TBTU in 50 ml THF.

C₂₇H₄₀N₄O₄S×C₂HF₃O₂ (587.65)

[M+H]+=474

HPLC (Method 2): retention time=3.03 min

EXAMPLE 26

Example 26 is prepared analogously to 1f from 0.20 g (0.66 mmol) of product from 22c, 0.14 g (0.73 mmol) of 4-(4-methylpiperazin-1-yl)-aniline (J. Med. Chem. SIR 48, 7, 2005, 2371-2387), 0.28 ml (1.99 mmol) of triethylamine and 0.21 g (0.66 mmol) of TBTU in 5 ml THF.

C₂₄H₃₄N₄O₄S×C₂HF₃O₂ (588.65)

[M+H]+=475

HPLC (Method 5): retention time=1.50 min

27a)

A mixture of 1.00 g (6.31 mmol) of 2-chloro-5-nitropyridine (Fluka), 1.32 ml (9.46 mmol) of triethylamine and 2 ml of methanol is taken and slowly combined with 1.13 g (8.83 mmol) of 4-dimethylamino-piperidine (Alfa Aesar). The reaction solution is then quenched with semisaturated sodium chloride, the precipitate formed is suction filtered and dried.

C₁₂H₁₈N₄O₂ (250.30)

27b)

27b is prepared analogously to 8b from 1.50 g (5.99 mmol) of product from 27a, 0.20 g palladium on charcoal (10%) and 15 ml of methanol.

C₁₂H₂₀N₄ (220.31)

27c)

A mixture of 0.11 g (0.35 mmol) of product from 22c and 2.0 ml of thionyl chloride is stirred for two hours at ambient temperature. The reaction mixture is then evaporated to dryness in vacuo.

C₁₃H₁₈ClNO₄S (319.81)

27d)

A mixture of 0.11 g (0.34 mmol) of product from 27c, 0.091 g (0.41 mmol) of product from 27b, 0.18 ml (1.03 mmol) of DIPEA and 45 ml THF is stirred for two hours at ambient temperature. The reaction mixture is then evaporated to dryness in vacuo. The crude product is purified by preparative HPLC. Then the hydrochloride is prepared using 4 M HCl in dioxane.

C₂₅H₃₇N₅O₄S×2HCl (576.58)

[M+H]+=504

HPLC (Method 2): retention time=2.73 min

EXAMPLE 28

28a)

A mixture of 1.50 g (6.84 mmol) of 1-(2-aminoethyl)-4-benzylpiperazine (Maybridge), 1.64 g (7.52 mmol) of Boc-anhydride and 30 ml dichloromethane is stirred for one hour at ambient temperature. Then the reaction solution is diluted with 100 ml dichloromethane and washed with 1 M sodium hydroxide solution and water. The organic phase is dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₈H₂₉N₃O₂ (319.44)

HPLC (Method 4): retention time=2.6 min

28b)

A mixture of 2.10 g (6.57 mmol) of product from 28a, 0.25 g palladium on charcoal (10%) and 30 ml of methanol is hydrogenated for 15 hours at ambient temperature in the autoclave. Then the catalyst is removed by suction filtering and the filtrate is evaporated to dryness in vacuo.

C₁₁H₂₃N₃O₄ (229.32)

[M+H]+=230

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.08

28c)

A mixture of 1.18 g (6.32 mmol) of 4-bromo-2,6-dimethylpyridine (Acta Chem. Scand. Ser. B 42, 1988, 373-377), 1.45 g (6.32 mmol) of product from 28b and 2.2 ml DIPEA is heated for 50 min to 130° C. in the microwave. The reaction mixture is combined with ethyl acetate and semisaturated potassium carbonate solution and then the phases are separated. The organic phase is dried on sodium sulphate and evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol/ammonia 95:5:0.5).

C₁₈H₃₀N₄O₂S (334.46)

[M+H]+=335

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.37

28d)

A mixture of 1.61 g (4.81 mmol) of product from 28c, 3.70 ml TFA and 30 ml dichloromethane is stirred for six hours at ambient temperature. The reaction mixture is then diluted with dichloromethane and washed with 5% sodium hydrogen carbonate solution. The aqueous phase is extracted twice more with ethyl acetate. The combined organic phases are dried on sodium sulphate and evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol/ammonia 90:10:1).

C₁₃H₂₂N₄ (234.34)

[M+H]+=235

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.10

28e)

Example 28 is prepared analogously to 1f from 0.11 g (0.35 mmol) of product from 22c, 0.082 g (0.35 mmol) of product from 28d, 0.098 ml (0.70 mmol) of triethylamine and 0.13 g (0.42 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₆H₃₉N₅O₄S (517.69)

[M+H]+=518

HPLC (Method 4): retention time=2.4 min

EXAMPLE 29

29a)

29a is prepared analogously to 28c from 0.12 g (0.80 mmol) of 4-chloropyridine hydrochloride (Aldrich), 0.20 g (0.80 mmol) of N-methyl-N-(2-piperidin-4-yl-ethyl)-benzamide (J. Med. Chem. 33, 1990, 1880-1887), 0.23 ml (1.68 mmol) of triethylamine in 5 ml of ethanol.

C₂₀H₂₅N₃O (323.43)

[M+H]+=324

29b)

A mixture of 0.52 g (1.61 mmol) of product from 29a, 10 ml of 2 M potassium hydroxide solution and 10 ml of ethanol is refluxed for 30 hours. The reaction mixture is evaporated down by half in vacuo and then extracted with dichloromethane. The organic extracts are dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₃H₂₁N₃ (219.33)

[M+H]+=220

TLC: silica gel, dichloromethane/methanol/ammonia 8:2:0.01, Rf value=0.46

29c)

Example 29 is prepared analogously to 1f from 0.14 g (0.46 mmol) of product from 22c, 0.10 g (0.46 mmol) of product from 29b, 0.15 ml (1.09 mmol) of triethylamine and 0.16 g (0.50 mmol) of TBTU in 30 ml THF and 5 ml DMF.

C₂₆H₃₈N₄O₄S×HCl (539.13)

[M+H]+=503

TLC: silica gel, dichloromethane/methanol/ammonia 8:2:0.01, Rf value=0.41

EXAMPLE 30

30a)

A mixture of 3.25 g (26.60 mmol) of 3,5-dimethylphenol (Aldrich), 3.20 g (28.52 mmol) of potassium-tert-butoxide and 40 ml DMSO is stirred for one hour at ambient temperature. Then 3.80 g (27.34 mmol) of bromoethylmethylether (Aldrich) is added dropwise thereto and the mixture is stirred for another two hours at ambient temperature. The reaction mixture is poured onto water and extracted with diethyl ether. The organic extracts are washed with water and saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₁H₁₆O₂ (180.24)

[M+H]+=181

TLC: silica gel, petroleum ether/ethyl acetate 9:1, Rf value=0.31

30b)

30b is prepared analogously to 13a from 4.30 g (23.86 mmol) of product from 30a and 5.60 g (48.06 mmol) of chlorosulphonic acid in 100 ml dichloromethane.

C₁₁H₁₅ClO₄S (278.75)

TLC: silica gel, petroleum ether/ethyl acetate 9:1, Rf value=0.06

30c)

30a is prepared analogously to 3a from 1.70 g (6.10 mmol) of product from 30b, 1.20 g (7.81 mmol) of β-alanine ethylester hydrochloride, 2.60 ml (18.65 mmol) of triethylamine in 30 ml dichloromethane.

C₁₆H₂₅NO₆S (359.44)

[M+H]+=360

TLC: silica gel, dichloromethane/methanol 19:1, Rf value=0.51

30d)

30d is prepared analogously to 3b from 1.90 g (5.29 mmol) of product from 30c, 1.10 g (7.75 mmol) of methyl iodide, 1.50 g (10.85 mmol) of anhydrous potassium carbonate in 30 ml DMF.

C₁₇H₂₇NO₆S (373.47)

[M+H]+=374

30e)

The acid is prepared analogously to 1c from 1.70 g (4.55 mmol) of product from 30d, 0.80 g (20.00 mmol) of sodium hydroxide in 30 ml of ethanol and 10 ml of water.

C₁₅H₂₃NO₆S (345.41)

[M+H]+=346

30f)

Example 30 is prepared analogously to 1f from 0.14 g (0.39 mmol) of product from 30e, 0.10 g (0.39 mmol) of product from 21b, 0.10 ml (0.99 mmol) of triethylamine and 0.14 g (0.44 mmol) of TBTU in 30 ml THF and 5 ml DMF.

C₂₉H₃₈N₆O₅S (582.72)

[M+H]+=583

TLC: silica gel, dichloromethane/methanol/ammonia 8:2:0.01, Rf value=0.44

EXAMPLE 31

Example 31 is prepared analogously to 1f from 0.16 g (0.46 mmol) of product from 30e, 0.10 g (0.46 mmol) of product from 29b, 0.11 ml (1.09 mmol) of triethylamine and 0.16 g (0.50 mmol) of TBTU in 30 ml THF and 5 ml DMF.

C₂₈H₄₂N₄O₅S×HCl (583.18)

[M+H]+=547

TLC: silica gel, dichloromethane/methanol/ammonia 8:2:0.01, Rf value=0.52

EXAMPLE 32

32a)

A mixture of 3.00 g (18.81 mmol) of 2-chloro-5-nitropyrimidine (Apin), 3.07 g (18.81 mmol) of 1-(4-pyridyl)-piperazine (Girindus), 9.40 ml (18.81 mmol) of 2 M sodium hydroxide solution in 80 ml dichloromethane is stirred for 2.5 hours at ambient temperature. Then the reaction mixture is diluted with 100 ml dichloromethane and washed with 5% sodium hydrogen carbonate solution. The organic phase is dried on sodium sulphate and evaporated to dryness in vacuo.

The crude product is triturated with a mixture of 50 ml of water and 30 ml ethyl acetate, filtered off and dried.

C₁₃H₁₄N₆O₂ (286.29)

[M+H]+=287

HPLC (Method 4): retention time=2.6 min

32b)

32b is prepared analogously to 21b from 1.93 g (6.74 mmol) of product from 32a and 0.3 g palladium on charcoal (10%) in 60 ml dichloromethane and 30 ml of methanol.

C₁₃H₁₆N₆ (256.31)

[M+H]+=257

TLC: silica gel, dichloromethane/methanol 8:2, Rf value=0.11

32c)

Example 32 is prepared analogously to 1f from 0.11 g (0.35 mmol) of product from 22c, 0.090 g (0.35 mmol) of product from 32b, 0.098 ml (0.70 mmol) of triethylamine and 0.13 g (0.42 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₆H₃₃N₇O₄S (539.65)

[M+H]+=540

HPLC (Method 4): retention time=2.9 min

EXAMPLE 33

33a)

A mixture of 0.68 g (2.91 mmol) of 4-(4-dimethylamino-piperidin-1-yl)-benzaldehyde (Tetrahedron 57, 2001, 4781-4785), 15 ml of 2 M ammonia in ethanol and 0.10 g Raney nickel is hydrogenated at ambient temperature in the autoclave. Then the catalyst is filtered off and the filtrate is evaporated to dryness in vacuo.

C₁₄H₂₃N₃ (233.35)

33b)

Example 33 is prepared analogously to 27d from 0.27 g (0.84 mmol) of product from 27c, 0.63 g (2.68 mmol) of product from 33a, 0.22 ml (1.26 mmol) of DIPEA in 3 ml dichloromethane.

C₂₇H₄₀N₄O₄S×2HCl (589.62)

[M+H]+=517

HPLC (Method 5): retention time=1.46 min

EXAMPLE 34

34a)

A mixture of 4.97 ml (59.50 mmol) of pyrrolidine and 100 ml dichloromethane is slowly combined with 5.00 g (23.80 mmol) of (4-bromomethyl-phenyl)-acetonitrile (Tetrahedron 47, 1991, 3969-3980) while cooling with an ice bath. Then the reaction mixture is heated to ambient temperature, washed with water, dried on magnesium sulphate and evaporated to dryness in vacuo.

C₁₃H₁₆N₂ (200.28)

[M+H]+=201

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.58

34b)

A mixture of 4.70 g (23.47 mmol) of product from 34a, 0.5 g Raney nickel and 50 ml of methanolic ammonia solution is hydrogenated in the autoclave at 50° C. Then the catalyst is filtered off and the filtrate is evaporated to dryness in vacuo.

C₁₃H₂₀N₂ (204.31)

[M+H]+=205

34c)

A mixture of 4.09 g (20.00 mmol) of product from 34b, 5.62 ml (40.00 mmol) of triethylamine and 100 ml dichloromethane is slowly combined with 2.17 ml (22.00 mmol) of ethyl chloroformate (Aldrich) while cooling with an ice bath. Then the mixture is stirred for five hours at ambient temperature. The reaction mixture is then quenched with water and extracted with MTB-ether. The organic extracts are washed twice with water, dried on magnesium sulphate and evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol/ammonia 9:1:0.1).

C₁₆H₂₄N₂O₂ (276.37)

[M+H]+=277

34d)

A mixture of 3.60 g (13.03 mmol) of product from 34c and 25 ml THF is slowly combined with 51.05 ml (51.05 mmol) of 1 M lithium aluminium hydride in THF (Aldrich). Then the mixture is stirred for two hours at ambient temperature and two hours at 70° C. The reaction mixture is then quenched with water and 15% sodium hydroxide solution and stirred for another hour at ambient temperature. The precipitate formed is filtered off and the filtrate is evaporated to dryness in vacuo.

The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol/ammonia 9:1:0.1).

C₁₄H₂₂N₂ (218.34)

[M+H]+=219

34e)

Example 34 is prepared analogously to 1f from 0.11 g (0.35 mmol) of product from 22c, 0.076 g (0.35 mmol) of product from 34d, 0.098 ml (0.70 mmol) of triethylamine and 0.13 g (0.42 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₇H₃₉N₃O₄S (501.68)

[M+H]+=502

HPLC (Method 4): retention time=3.1 min

EXAMPLE 35

35a)

A mixture of 0.33 g (2.34 mmol) of 1-fluoro-4-nitrobenzene (Aldrich), 0.30 g (2.34 mmol) of 3-dimethylamino-piperidine (Chess), 0.46 ml (3.27 mmol) of triethylamine and 4 ml DMF is stirred for six hours at ambient temperature. The reaction mixture is then quenched with water and extracted with dichloromethane. The organic extracts are washed with saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₃H₁₉N₃O₂ (249.31)

[M+H]+=250

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.56

35b)

A mixture of 0.25 g (1.00 mmol) of product from 35a, 30 mg Raney nickel and 10 ml ethyl acetate is hydrogenated in the autoclave at ambient temperature. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo.

C₁₃H₂₁N₃ (219.33)

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.25

35c)

Example 35 is prepared analogously to 1f from 0.16 g (0.50 mmol) of product from 1c, 0.11 g (0.50 mmol) of product from 35b, 0.14 ml (1.00 mmol) of triethylamine and 0.16 g (0.50 mmol) of TBTU in 3 ml DMF.

C₂₃H₃₀Cl₂N₄O₃S×HCl (539.14)

[M+H]+=513/515/517

HPLC (Method 1): retention time=2.43 min

EXAMPLE 36

36a)

A mixture of 2.50 g (13.35 mmol) of 3-piperazin-1-yl-benzonitrile (Tetrahedron 55, 1999, 13285-13300), 3.00 g (13.75 mmol) of Boc-anhydride, 2.40 ml (13.78 mmol) of DIPEA and 50 ml THF is stirred for four hours at ambient temperature and then evaporated to dryness in vacuo. The residue is taken up in water and extracted with diethyl ether. The organic extracts are dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₆H₂₁N₃O₂ (287.36)

[M+Na]+=310

36b)

36b is prepared analogously to 34b from 4.40 g (15.31 mmol) of product from 36a, 0.7 g Raney nickel and 45 ml of methanolic ammonia solution.

C₁₆H₂₅N₃O₂ (291.39)

[M+H]+=292

36c)

36c is prepared analogously to 1f from 0.40 g (1.33 mmol) of product from 22c, 0.43 g (1.46 mmol) of product from 36b, 0.56 ml (3.98 mmol) of triethylamine and 0.43 g (1.33 mmol) of TBTU in 10 ml THF.

C₂₉H₄₂N₄O₆S (574.73)

M+H]+=575

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.53

36d)

Example 36 is prepared analogously to 18b from 0.50 g (0.57 mmol) of product from 36c, 0.44 ml TFA in 5 ml dichloromethane.

C₁₈H₂₈Cl₂N₄O₃S×C₂HF₃O₂ (588.64)

[M+H]+=475

HPLC (Method 2): retention time=2.95 min

EXAMPLE 37

37a)

A mixture of 2.00 g (12.25 mmol) of 1-(4-pyridyl)-piperazine (Girindus), 1.65 g (14.70 mmol) of potassium-tert-butoxide and 50 ml DMSO is stirred for 30 min at ambient temperature and then combined with 2.25 g (12.25 mmol) of 1-benzylmethylamino-2-chloroethane (Chem. Pharm. Bull. 45, 1997, 996-1007). The reaction mixture is stirred overnight at ambient temperature and then poured onto ice water. It is extracted four times with dichloromethane. The organic extracts are dried on sodium sulphate and evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol/ammonia 9:1:0.1).

C₁₉H₂₆N₄ (310.44)

[M+H]+=311

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.22

37b)

A mixture of 1.78 g (5.73 mmol) of product from 37a, 0.40 g palladium hydroxide and 50 ml of methanol is hydrogenated at 40° C. in the autoclave. The catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol/ammonia 9:1:0.1).

C₁₂H₂₀N₄ (220.31)

[M+H]+=221

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.13

37c)

Example 37 is prepared analogously to 1f from 0.11 g (0.35 mmol) of product from 22c, 0.072 g (0.35 mmol) of product from 37b, 0.098 ml (0.70 mmol) of triethylamine and 0.13 g (0.42 mmol) of TBTU in 7 ml THF.

C₂₅H₃₇N₅O₄S×2HCl (576.58)

[M+H]+=504

HPLC (Method 4): retention time=2.5 min

EXAMPLE 38

38a)

A mixture of 4.44 g (33.29 mmol) of aluminium chloride (Merck) and 16 ml of dichloroethane is taken and 1.24 ml (17.44 mmol) of acetyl chloride (Aldrich) is slowly added while cooling with an ice bath. The mixture is stirred for 30 min at ambient temperature. Then 3.00 g (15.85 mmol) of 1-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-ethanone (J. Med. Chem. 46, 2003, 4952-4964) in 7 ml of dichloroethane slowly added to the reaction mixture. After two hours' stirring at ambient temperature the reaction mixture is poured onto a mixture of 6 M HCl and ice. After the phase separation the aqueous phase is extracted another three times with dichloromethane. The combined organic phases are washed with water, dried on sodium sulphate and evaporated to dryness in vacuo.

The crude product thus obtained is triturated with diethyl ether, filtered off and dried.

C₁₄H₁₇NO₂ (231.29)

[M+H]+=232

38b)

A mixture of 2.86 g (12.37 mmol) of product from 38a and 79 ml 2.5 M sodium hydroxide solution is slowly combined at ambient temperature with 2.48 ml (48.23 mmol) of bromine. The reaction mixture is then stirred for one hour at ambient temperature. The precipitate formed is filtered off and the filtrate is extracted with MTB-ether. The aqueous phase is then mixed with concentrated HCl and a little sodium disulphite solution while cooling with an ice bath. The precipitate formed is filtered off and dried in the circulating air dryer at 30° C.

C₁₃H₁₅NO₃ (233.26)

[M+H]+=234

38c)

A mixture of 2.12 g (9.09 mmol) of product from 38b and 20 ml 6 M HCl is heated for 3.5 days to 100° C. The reaction mixture is then cooled with a mixture of ice and ethanol. The precipitate formed is filtered off, washed with a little cooled acetone and diethyl ether and dried in the desiccator.

C₁₁H₁₃NO₂×HCl (227.69)

[M+H]+=192

38d)

First 0.94 ml (17.83 mmol) of 50% sodium hydroxide solution, then 2.66 ml (35.66 mmol) of 37% formalin solution are slowly added to a mixture of 2.03 g (8.92 mmol) of product from 38c and 3.36 ml (89.16 mmol) of formic acid. The reaction mixture is heated for two hours to 70° C. and then evaporated to dryness in vacuo. The residue is combined with water and concentrated HCl and again evaporated to dryness. The crude product is triturated with a little ice-cold water, filtered off and dried in the circulating air dryer at 60° C.

C₁₂H₁₅NO₂×HCl (241.71)

[M+H]+=206

38e)

38e is prepared analogously to 1f from 2.00 g (8.27 mmol) of product from 38d, 18.20 ml (9.10 mmol) of ammonia 0.5 M in dioxane (Aldrich), 3.46 ml (24.82 mmol) of triethylamine and 3.19 g (9.93 mmol) of TBTU in 30 ml THF.

C₁₂H₁₆N₂O (204.27)

[M+H]+=205

HPLC (Method 2): retention time=1.54 min

38f)

A mixture of 5.20 ml (5.20 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) and 18 ml THF is heated to 50° C. and slowly combined with 0.84 g (2.64 mmol) of product from 38e. The reaction mixture is then stirred for 30 min at 50° C. It is then cooled to −20° C. and the reaction mixture is quenched first with a mixture of water and THF, then with 2 M sodium hydroxide solution. It is stirred for one hour at ambient temperature. The precipitate formed is filtered off, the filtrate is evaporated to dryness in vacuo. The residue is taken up in dichloromethane and washed with saturated sodium hydrogen sulphate solution. The organic phase is dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₂H₁₈N₂ (190.28)

[M+H]+=191

HPLC (Method 2): retention time=2.21 min

38g)

Example 38 is prepared analogously to 1f from 0.19 g (0.63 mmol) of product from 22c, 0.12 g (0.63 mmol) of product from 38f, 0.26 ml (1.89 mmol) of triethylamine and 0.20 g (0.63 mmol) of TBTU in 5 ml THF.

C₂₅H₃₅N₃O₄S×C₂HF₃O₂ (587.65)

[M+H]+=474

HPLC (Method 4): retention time=2.98 min

EXAMPLE 39

39a)

A mixture of 1.50 g (6.07 mmol) of benzyl 4-oxo-azepan-1-carboxylate (Tyger), 20 ml (40.00 mmol) of dimethylamine 2 M in THF (Aldrich) and 0.34 ml (6.07 mmol) of acetic acid is stirred for 20 min at ambient temperature and then combined with 3.82 g (18.00 mmol) of sodium triacetoxyborohydride (Aldrich). The mixture is stirred overnight at ambient temperature. The reaction mixture is then mixed with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic extracts are washed with saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/4-12% (methanol+10% ammonia)).

C₁₆H₂₄N₂O₂ (276.37)

[M+H]+=277

HPLC (Method 1): retention time=2.12 min

39b)

A mixture of 1.00 g (3.62 mmol) of product from 39a, 0.10 g palladium on charcoal (10%) and 30 ml of methanol is hydrogenated at ambient temperature in the autoclave. The catalyst is then filtered off, the filtrate is evaporated to dryness in vacuo.

C₈H₁₈N₂ (142.24)

[M+H]+=143

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.12

39c)

39c is prepared analogously to 1d from 0.56 g (4.37 mmol) of product from 39b, 0.64 g (4.50 mmol) of 4-fluoro-nitrobenzene (Aldrich), 0.65 ml (4.60 mmol) of triethylamine in 5 ml DMF.

C₁₄H₂₁N₃O₂ (263.34)

[M+H]+=264

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.60

39d)

39d is prepared analogously to 8b from 0.94 g (3.55 mmol) of product from 39c and 0.10 g palladium on charcoal (10%) in 30 ml of methanol.

C₁₄H₂₃N₃O₂ (233.35)

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.15

39e)

Example 39 is prepared analogously to 1f from 0.30 g (1.00 mmol) of product from 22c, 0.23 g (1.00 mmol) of product from 39d, 0.42 ml (3.00 mmol) of triethylamine and 0.32 g (1.00 mmol) of TBTU in 15 ml DMF.

C₂₇H₄₀N₄O₄S×HCl (553.16)

[M+H]+=517

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.42

HPLC (Method 5): retention time=1.50 min

EXAMPLE 40

Example 40 is prepared analogously to 1f from 0.16 g (0.50 mmol) of product from 1c, 0.12 g (0.50 mmol) of product from 39d, 0.21 ml (1.50 mmol) of triethylamine and 0.16 g (0.50 mmol) of TBTU in 5 ml DMF.

C₂₄H₃₂Cl₂N₄O₃S×HCl (563.97)

[M+H]+=527/529/531

TLC: silica gel, dichloromethane/methanol/ammonia 6:1:0.2, Rf value=0.48

HPLC (Method 5): retention time=1.53 min

EXAMPLE 41

41a)

41a is prepared analogously to 1d from 1.00 g (5.87 mmol) of diethyl-piperidin-4-ylmethyl-amine (Chem. Pharm. Bull. 42, 1994, 74-84), 0.83 g (5.87 mmol) of 4-fluoro-nitrobenzene (Aldrich), 1.14 ml (8.20 mmol) of triethylamine in 12 ml DMF.

C₁₆H₂₅N₃O₂ (291.39)

[M+H]+=292

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.5

41b)

A mixture of 0.40 g (1.37 mmol) of product from 41a, 0.10 g palladium on charcoal (10%) and 30 ml of methanol is hydrogenated at ambient temperature in the autoclave. The catalyst is then filtered off, the filtrate is evaporated to dryness in vacuo.

C₁₆H₂₇N₃ (261.41)

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.1

41c)

Example 41 is prepared analogously to 1f from 0.40 g (1.34 mmol) of product from 22c, 0.35 g (1.34 mmol) of product from 41b, 0.47 ml (3.35 mmol) of triethylamine and 0.43 g (1.34 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₉H₄₄N₄O₄S×HCl (581.21)

[M+H]+=545

HPLC (Method 5): retention time=1.42 min

EXAMPLE 42

42a)

42a is prepared analogously to 1d from 1.88 g (12.00 mmol) of dimethyl-(2-piperidin-4-yl-ethyl)-amine (J. Med. Chem. 36, 1993, 162-165), 1.69 g (12.00 mmol) of 4-fluoro-nitrobenzene (Aldrich), 2.37 ml (17.00 mmol) of triethylamine in 15 ml DMF.

C₁₅H₂₃N₃O₂ (277.36)

[M+H]+=278

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.2

42b)

A mixture of 0.30 g (1.08 mmol) of product from 42a, 0.10 g palladium on charcoal (10%) and 30 ml of methanol is hydrogenated at ambient temperature in the autoclave. The catalyst is then filtered off, the filtrate is evaporated to dryness in vacuo.

C₁₅H₂₅N₃ (247.38)

42c)

Example 42 is prepared analogously to 1f from 0.33 g (1.08 mmol) of product from 22c, 0.27 g (1.08 mmol) of product from 42b, 0.38 ml (2.70 mmol) of triethylamine and 0.35 g (1.08 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₈H₄₂N₄O₄S (530.72)

[M+H]+=531

HPLC (Method 5): retention time=1.41 min

EXAMPLE 43

A mixture of 0.15 g (0.25 mmol) of product from 36d, 0.025 ml (0.40 mmol) of methyl iodide (Aldrich), 0.10 ml (0.75 mmol) of potassium carbonate and 5 ml acetonitrile is stirred overnight at ambient temperature. The reaction mixture is then combined with 10% TFA, the product is separated off by preparative HPLC.

C₂₅H₃₆N₄O₄S×C₂HF₃O₂ (602.67)

[M+H]+=489

HPLC (Method 2): retention time=2.99 min

EXAMPLE 44

44a)

A mixture of 0.72 g (4.61 mmol) of dimethyl-(2-piperidin-4-yl-ethyl)-amine (J. Med. Chem. 36, 1993, 162-165), 0.73 g (4.61 mmol) of 2-chloro-5-nitropyridine (Fluka), 1.30 g (9.41 mmol) of potassium carbonate and 100 ml THF is stirred at ambient temperature over the weekend. The precipitate is filtered off, the filtrate is evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol 19:1 to 4:1).

C₁₄H₂₂N₄O₂ (278.35)

[M+H]+=279

44b)

A mixture of 0.26 g (0.93 mmol) of product from 44a, 0.05 g palladium on charcoal (10%) and 30 ml of methanol is hydrogenated at ambient temperature in the autoclave. The catalyst is then filtered off, the filtrate is evaporated to dryness in vacuo.

C₁₄H₂₄N₄ (248.37)

[M+H]+=249

44c)

Example 44 is prepared analogously to 1f from 0.12 g (0.40 mmol) of product from 22c, 0.10 g (0.40 mmol) of product from 44b, 0.069 ml (0.50 mmol) of triethylamine and 0.14 g (0.44 mmol) of TBTU in 40 ml THF and 5 ml DMF.

C₂₇H₄₁N₅O₄S×2HCl (604.63)

[M+H]+=532

HPLC (Method 5): retention time=1.40 min

EXAMPLE 45

45a)

45a is prepared analogously to 44a from 1.00 g (5.87 mmol) of diethyl-piperidin-4-ylmethyl-amine (Chem. Pharm. Bull. 42, 1994, 74-84), 0.93 g (5.87 mmol) of 2-chloro-5-nitropyridine (Fluka) and 1.70 g (12.30 mmol) of potassium carbonate in 100 ml THF.

C₁₅H₂₄N₄O₂ (292.38)

[M+H]+=293

45b)

A mixture of 0.20 g (0.68 mmol) of product from 45a, 0.03 g palladium on charcoal (10%) and 30 ml of methanol is hydrogenated at ambient temperature in the autoclave. The catalyst is then filtered off, the filtrate is evaporated to dryness in vacuo.

C₁₅H₂₆N₄ (262.39)

[M+H]+=263

45c)

Example 45 is prepared analogously to 1f from 0.16 g (0.53 mmol) of product from 22c, 0.14 g (0.53 mmol) of product from 45b, 0.096 ml (0.69 mmol) of triethylamine and 0.19 g (0.58 mmol) of TBTU in 40 ml THF and 5 ml DMF.

C₂₈H₄₃N₅O₄S×2HCl (618.66)

[M+H]+=546

HPLC (Method 5): retention time=1.40 min

EXAMPLE 46

46a)

46a is prepared analogously to 1d from 3.00 g (15.21 mmol) of 2-piperazin-1-yl-1-pyrrolidin-1-yl-ethanone (Chess), 2.15 g (15.21 mmol) of 1-fluoro-4-nitrobenzene (Aldrich) and 3.07 ml (22.00 mmol) of triethylamine in 25 ml DMF.

C₁₆H₂₂N₄O₃ (318.37)

[M+H]+=319

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.4

46b)

A mixture of 3.00 g (9.42 mmol) of product from 46a, 0.30 g palladium on charcoal (10%) and 200 ml of methanol is hydrogenated at ambient temperature in the autoclave. The catalyst is then filtered off, the filtrate is evaporated to dryness in vacuo.

C₁₆H₂₄N₄O (288.39)

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.42

46c)

30.00 ml (30.00 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) is placed in 50 ml THF and at ambient temperature combined with a mixture of 2.70 g (9.36 mmol) of product from 46b and 20 ml THF. The reaction mixture is then stirred for three hours at ambient temperature and then combined with 20% sodium hydroxide solution while cooling with an ice bath. The precipitate formed is filtered off, the filtrate is evaporated to dryness in vacuo.

C₁₆H₂₆N₄ (274.40)

46d)

Example 46 is prepared analogously to 1f from 0.30 g (1.00 mmol) of product from 22c, 0.27 g (1.00 mmol) of product from 46c, 0.35 ml (2.50 mmol) of triethylamine and 0.32 g (1.00 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₉H₄₃N₅O₄S×HCl (594.21)

[M+H]+=558

HPLC (Method 5): retention time=1.43 min

EXAMPLE 47

Example 47 is prepared analogously to 1f from 0.20 g (0.66 mmol) of product from 22c, 0.14 g (0.66 mmol) of 4-(4-methyl-piperazin-1-ylmethyl)-phenylamine (Med. Chem. Res. 9, 1999, 149-161), 0.28 ml (1.99 mmol) of triethylamine and 0.21 g (0.66 mmol) of TBTU in 5 ml THF.

C₂₅H₃₆N₄O₄S (488.64)

[M+H]+=489

HPLC (Method 5): retention time=1.42 min

EXAMPLE 48

48a)

48a is prepared analogously to 1f from 0.24 g (1.45 mmol) of 4-nitrobenzoic acid (Aldrich), 0.19 g (1.45 mmol) of 4-dimethylamino-piperidine (Alfa Aesar), 0.21 ml (1.52 mmol) of triethylamine and 0.49 g (1.52 mmol) of TBTU in 8 ml DMF.

C₁₄H₁₉N₃O₃×C₂HF₃O₂ (391.34)

[M+H]+=278

HPLC (Method 2): retention time=2.29 min

48b)

A mixture of 0.36 g (0.92 mmol) of product from 48a, 0.092 g palladium on charcoal (10%) and 5 ml of methanol is hydrogenated at ambient temperature in the autoclave. The catalyst is then filtered off, the filtrate is evaporated to dryness in vacuo.

C₁₄H₂₁N₃O×C₂HF₃O₂ (361.36)

[M+H]+=248

HPLC (Method 2): retention time=0.66 min

48c)

Example 48 is prepared analogously to 1f from 0.15 g (0.50 mmol) of product from 22c, 0.18 g (0.50 mmol) of product from 48b, 0.21 ml (1.49 mmol) of triethylamine and 0.16 g (0.50 mmol) of TBTU in 3 ml THF.

C₂₇H₃₈N₄O₅S×C₂HF₃O₂ (644.70)

[M+H]+=531

HPLC (Method 5): retention time=1.48 min

EXAMPLE 49

Example 49 is prepared analogously to 1f from 0.15 g (0.50 mmol) of product from 22c, 0.11 g (0.50 mmol) of (4-aminophenyl)-(4-methylpiperazin-1-yl)-methanone (J. Org. Chem. 24, 1959, 459-463), 0.21 ml (1.49 mmol) of triethylamine and 0.16 g (0.50 mmol) of TBTU in 3 ml THF.

C₂₅H₃₄N₄O₅S×C₂HF₃O₂ (616.65)

[M+H]+=503

HPLC (Method 5): retention time=1.47 min

EXAMPLE 50

50a)

50a is prepared analogously to 1f from 0.60 g (4.34 mmol) of 5-amino-pyridine-2-carboxylic acid (Pharm. Acta Helv. 44, 1969, 637-643), 0.56 g (4.34 mmol) of 4-dimethylamino-piperidine (Alfa Aesar), 0.64 ml (4.56 mmol) of triethylamine and 1.46 g (4.56 mmol) of TBTU in 24 ml DMF.

C₁₃H₂₀N₄O×2C₂HF₃O₂ (476.37)

HPLC (Method 2): retention time=0.65 min

50b)

A mixture of 0.64 g (1.99 mmol) of product from 27c, 1.90 g (2.39 mmol) of product from 50a, 0.08 g (0.33 mmol) of DMAP and 16 ml chlorobenzene is heated to 15° C. for 39 hours. The reaction mixture is then evaporated to dryness in vacuo. The product is obtained by preparative HPLC.

C₂₆H₃₇N₅O₅S×C₂HF₃O₂ (645.69)

[M+H]+=532

HPLC (Method 5): retention time=1.44 min

EXAMPLE 51

51a)

A mixture of 0.26 g (1.11 mmol) of product from 39d, 0.27 g (1.22 mmol) of Boc-anhydride, 0.17 ml (1.22 mmol) of triethylamine and 15 ml dichloromethane is stirred overnight at ambient temperature. Then the reaction mixture is diluted with dichloromethane, washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₉H₃₁N₃O₂ (333.47)

[M+H]+=334

HPLC (Method 1): retention time=2.40 min

51b)

0.13 g (3.40 mmol) of lithium aluminium hydride are placed in 5 ml THF, heated to 60° C. and combined with 0.38 g (1.14 mmol) of product from 51a in 5 ml THF. The reaction mixture is then refluxed for four hours and stirred overnight at ambient temperature. Then the reaction mixture is quenched with water and 1 M sodium hydroxide solution. The precipitate formed is filtered off through Celite, the filtrate is evaporated to dryness in vacuo.

C₁₅H₂₅N₃ (247.38)

TLC: silica gel, dichloromethane/methanol/ammonia 4:1:0.2, Rf value=0.68

51c)

Example 51 is prepared analogously to 1f from 0.15 g (0.50 mmol) of product from 22c, 0.12 g (0.50 mmol) of product from 51b, 0.21 ml (1.50 mmol) of triethylamine and 0.18 g (0.55 mmol) of TBTU in 8 ml DMF.

C₂₈H₄₂N₄O₄S×HCl (567.18)

[M+H]+=531

HPLC (Method 1): retention time=2.5 min

EXAMPLE 52

52a)

0.70 ml (7.36 mmol) of acetic anhydride are placed under a nitrogen atmosphere and slowly combined with 0.42 ml (9.06 mmol) of formic acid while cooling with an ice bath. The reaction mixture is heated for two hours to 50-60° C. and then combined with 0.50 g (2.28 mmol) of product from 8b in 7 ml dichloromethane while cooling with an ice bath. After 20 minutes' stirring at ambient temperature the reaction mixture is evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol/ammonia 9:1:0.1).

C₁₄H₂₁N₃O (247.34)

[M+H]+=248

HPLC (Method 5): retention time=0.50 min

52b)

52b is prepared analogously to 51b from 0.17 g (4.51 mmol) of lithium aluminium hydride and 0.58 g (2.34 mmol) of product from 52a in 10 ml THF.

C₁₄H₂₃N₃ (233.35)

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.5

52c)

Example 52 is prepared analogously to 1f from 0.21 g (0.68 mmol) of product from 22c, 0.24 g (0.68 mmol) of product from 52b, 0.28 ml (2.04 mmol) of triethylamine and 0.22 g (0.68 mmol) of TBTU in 4 ml THF.

C₂₇H₄₀N₄O₄S×C₂HF₃O₂ (630.72)

[M+H]+=517

HPLC (Method 5): retention time=1.50 min

EXAMPLE 53

53a)

53a is prepared analogously to 3a from 4.50 g (19.17 mmol) of product from 13a, 1.69 g (21.10 mmol) of N-methylaminoethanol (BASF), 6.68 ml (47.90 mmol) of triethylamine in 150 ml dichloromethane.

C₁₂H₁₉NO₄S (273.35)

[M+H]+=274

TLC: silica gel, dichloromethane/ethanol 19:1, Rf value=0.43

53b)

First 100 ml 35% sodium hydroxide solution, then 4.18 ml (28.26 mmol) of tert-butyl bromoacetate in 20 ml of toluene are added to a mixture of 5.15 g (18.84 mmol) of product from 53a, 1.75 g (6.60 mmol) of tetrabutylammonium chloride (Fluka) and 80 ml of toluene at 0° C. The reaction mixture is then stirred for 1.5 hours at ambient temperature, then diluted with diethyl ether. After the phase separation the organic phase is washed four times with water until neutral, dried on sodium sulphate and evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: petroleum ether/ethyl acetate 4:1).

C₁₈H₂₉NO₆S (387.49)

[M+H]+=388

TLC: silica gel, petroleum ether/ethyl acetate 7:3, Rf value=0.59

53c)

A mixture of 6.80 g (17.55 mmol) of product from 53b, 8 ml TFA and 100 ml dichloromethane is stirred for 2.5 hours at ambient temperature. The reaction mixture is then evaporated to dryness in vacuo. The residue is combined with 1 M sodium hydroxide solution and extracted twice with ethyl acetate (organic extracts are discarded). The aqueous phase is acidified with 2 M HCl, then extracted again with ethyl acetate. The organic extracts are washed with water, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₄H₂₁NO₆S (331.29)

[M+H]+=332

HPLC (Method 4): retention time=3.4 min

53d)

53d is prepared analogously to 28c from 1.00 g (6.10 mmol) of 4-chloro-2-methylpyridine hydrochloride (Alfa Aesar) and 2.08 g (12.20 mmol) of N-methyl-N-piperidin-4-ylmethyl-acetamide (DE 1100635, Rhône-Poulenc, 1961).

C₁₅H₂₃N₃O (261.36)

[M+H]+=262

HPLC (Method 4): retention time=1.9 min

53e)

A mixture of 1.37 g (5.24 mmol) of product from 53d and 15 ml semiconcentrated HCl is refluxed for four days. The reaction mixture is made alkaline with 20% sodium hydroxide solution and extracted with dichloromethane. The organic extracts are dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₃H₂₁N₃ (219.33)

[M+H]+=220

TLC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.48

53f)

Example 53 is prepared analogously to 1f from 0.099 g (0.30 mmol) of product from 53c, 0.066 g (0.30 mmol) of product from 53e, 0.10 ml (0.75 mmol) of triethylamine and 0.12 g (0.36 mmol) of TBTU in 8 ml THF and 1 ml DMF.

C₂₇H₄₀N₄O₅S×HCl (569.16)

[M+H]+=533

HPLC (Method 4): retention time=3.1 min

EXAMPLE 54

54a)

54a is prepared analogously to 1f from 2.00 g (8.27 mmol) of product from 38d, 8.28 ml (16.55 mmol) of methylamine 2 M in THF (Aldrich), 3.46 ml (24.82 mmol) of triethylamine and 3.19 g (9.93 mmol) of TBTU in 30 ml THF.

C₁₃H₁₈N₂O (218.29)

[M+H]+=219

TLC: silica gel, dichloromethane/methanol 8:2, Rf value=0.14

54b)

54b is prepared analogously to 38f from 1.00 g (4.58 mmol) of product from 54a and 9.00 ml (9.00 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 30 ml THF.

C₁₃H₂₀N₂ (204.31)

[M+H]+=205

TLC: silica gel, dichloromethane/methanol 8:2, Rf value=0.07

54c)

Example 54 is prepared analogously to 1f from 0.099 g (0.30 mmol) of product from 53c, 0.088 g (0.30 mmol) of product from 54b, 0.10 ml (0.75 mmol) of triethylamine and 0.12 g (0.36 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₇H₃₉N₃O₅S×HCl (554.14)

[M+H]+=518

HPLC (Method 4): retention time=3.1 min

EXAMPLE 55

55a)

A mixture of 3.20 g (34.00 mmol) of 2-aminopyridine (Aldrich), 2.75 g (11.31 mmol) of 4-bromoacetylbenzoic acid (Fluorochem) and 100 ml of ethanol is refluxed for six hours at reflux temperature and stirred overnight at ambient temperature. The precipitate formed is filtered off and dried.

C₁₄H₁₀N₂O₂ (238.24)

[M+H]+=239

55b)

55b is prepared analogously to 27c from 1.7 g (7.14 mmol) of product from 55a and 30 ml of thionyl chloride.

C₁₄H₉ClN₂O×HCl (293.15)

55c)

2.10 g (7.14 mmol) of product from 55b in 100 ml dichloromethane are combined with 25 ml (50.00 mmol) of methylamine 2 M in THF (Aldrich) while cooling with an ice bath. The reaction mixture is then stirred for two hours at ambient temperature and then evaporated to dryness in vacuo. The residue is triturated with water, filtered off and dried. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol 97:3).

C₁₅H₁₃N₃O (251.28)

[M+H]+=252

55d)

A mixture of 0.70 g (2.79 mmol) of product from 55c, 0.15 g palladium on charcoal (20%), 100 ml of methanol and 30 ml dichloromethane is hydrogenated at ambient temperature in the autoclave. The catalyst is filtered off, the filtrate is evaporated to dryness in vacuo.

C₁₅H₁₇N₃O (255.32)

[M+H]+=256

55e)

55e is prepared analogously to 38f from 0.80 g (3.13 mmol) of product from 55d and 20.00 ml (20.00 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 50 ml of pyridine.

C₁₅H₁₉N₃ (241.33)

[M+H]+=242

55f)

Example 55 is prepared analogously to 1f from 0.14 g (0.42 mmol) of product from 53c, 0.10 g (0.41 mmol) of product from 55e, 0.14 ml (0.99 mmol) of triethylamine and 0.15 g (0.46 mmol) of TBTU in 30 ml THF and 5 ml DMF.

C₂₉H₃₈N₄O₅S×HCl (591.16)

[M+H]+=555

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.26

EXAMPLE 56

56a)

56a is prepared analogously to 27c from 1.35 g (5.59 mmol) of 1-benzyl-pyrrolidine-3-carboxylic acid (J. Org. Chem. 33, 1968, 3637-3639) and 10 ml of thionyl chloride.

C₁₂H₁₄ClNO×HCl (260.16)

56b)

56b is prepared analogously to 55c from 1.45 g (5.57 mmol) of product from 56a, 10 ml (50.00 mmol) of methylamine 2 M in THF (Aldrich) in 50 ml THF.

C₁₃H₁₈N₂O (218.29)

[M+H]+=219

56c)

A mixture of 1.10 g (5.04 mmol) of product from 56b, 0.20 g palladium hydroxide and 40 ml of methanol is hydrogenated at 50° C. in the autoclave. The catalyst is filtered off, the filtrate is evaporated to dryness in vacuo.

C₆H₁₂N₂O (128.17)

[M+H]+=129

56d)

56d is prepared analogously to 28c from 0.76 g (5.08 mmol) of 4-chloropyridine hydrochloride (Aldrich), 0.65 g (5.07 mmol) of product from 56c and 1.52 ml (10.88 mmol) of triethylamine in 10 ml of ethanol.

C₁₁H₁₅N₃O (205.26)

[M+H]+=206

56e)

56e is prepared analogously to 38f from 0.45 g (2.19 mmol) of product from 56d and 7.00 ml (7.00 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 30 ml THF.

C₁₁H₁₇N₃ (191.27)

[M+H]+=192

56f)

Example 56 is prepared analogously to 1f from 0.14 g (0.42 mmol) of product from 53c, 0.10 g (0.42 mmol) of product from 56e, 0.18 ml (1.29 mmol) of triethylamine and 0.18 g (0.56 mmol) of TBTU in 30 ml THF and 5 ml DMF.

C₂₅H₃₆N₄O₅S×HCl (541.10)

[M+H]+=505

HPLC (Method 5): retention time=1.51 min

EXAMPLE 57

Example 57 is prepared analogously to 1f from 0.10 g (0.30 mmol) of product from 53c, 0.066 g (0.30 mmol) of product from 8b, 0.13 ml (0.91 mmol) of triethylamine and 0.097 g (0.30 mmol) of TBTU in 5 ml DMF.

C₂₇H₄₀N₄O₅S×C₂HF₃O₂ (646.72)

[M+H]+=533

HPLC (Method 5): retention time=1.51 min

EXAMPLE 58

Example 58 is prepared analogously to 1f from 0.10 g (0.30 mmol) of product from 53c, 0.07 g (0.30 mmol) of product from 33a, 0.13 ml (0.91 mmol) of triethylamine and 0.097 g (0.30 mmol) of TBTU in 5 ml DMF.

C₂₈H₄₂N₄O₅S×C₂HF₃O₂ (660.75)

[M+H]+=547

HPLC (Method 5): retention time=1.48 min

EXAMPLE 59

59a)

59a is prepared analogously to 1f from 2.00 g (11.16 mmol) of terephthalic acid monomethylamide (EMKA), 1.90 ml (22.32 mmol) of isopropylamine (Aldrich), 3.11 ml (22.32 mmol) of triethylamine and 4.30 g (13.40 mmol) of TBTU in 60 ml THF.

C₁₂H₁₆N₂O₂ (220.27)

[M+H]+=221

HPLC (Method 4): retention time=2.3 min

59b)

59b is prepared analogously to 38f from 1.34 g (6.08 mmol) of product from 59a and 25.00 ml (25.00 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 150 ml THF.

C₁₂H₂₀N₂ (192.30)

[M+H]+=193

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.17

59c)

Example 59 is prepared analogously to 1f from 0.099 g (0.30 mmol) of product from 53c, 0.058 g (0.30 mmol) of product from 59b, 0.10 ml (0.75 mmol) of triethylamine and 0.12 g (0.36 mmol) of TBTU in 8 ml THF.

C₂₆H₃₉N₃O₅S×HCl (542.13)

[M+H]+=506

HPLC (Method 4): retention time=3.1 min

EXAMPLE 60

60a)

A mixture of 3.00 g (13.91 mmol) of methyl 4-aminoethylbenzoate (EMKA), 1.94 ml (13.91 mmol) of triethylamine and 50 ml THF is stirred for 10 min at ambient temperature and then combined with 1.13 ml (15.30 mmol) of acetone. The reaction mixture is stirred for another 30 min at ambient temperature, then 3.24 g (15.30 mmol) of sodium triacetoxyborohydride and 1.19 ml (20.86 mmol) of acetic acid are added. The mixture is stirred for 16 hours at ambient temperature. The reaction mixture is evaporated to dryness in vacuo, the residue is taken up in 1 M HCl and extracted with ethyl acetate (organic phase is discarded). The aqueous phase is made alkaline with saturated potassium carbonate solution and extracted with ethyl acetate. The organic extracts are dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₃H₁₉NO₂ (221.30)

[M+H]+=222

HPLC (Method 4): retention time=2.2 min

60b)

A mixture of 2.52 g (11.39 mmol) of product from 60a, 11.40 ml (22.80 mmol) of methylamine 2 M in THF (Aldrich), 0.54 g (5.70 mmol) of magnesium chloride (Aldrich) and 100 ml THF is stirred for 17 hours at 120° C. in the autoclave. The reaction mixture is filtered, the filtrate is evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol/ammonia 9:1:0.1).

C₁₃H₂₀N₂O (220.31)

[M+H]+=221

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.21

60c)

60c is prepared analogously to 38f from 1.49 g (6.76 mmol) of product from 60b and 10.00 ml (10.00 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 60 ml THF.

C₁₃H₂₂N₂ (206.33)

[M+H]+=207

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.10

60d)

Example 60 is prepared analogously to 1f from 0.099 g (0.30 mmol) of product from 53c, 0.062 g (0.30 mmol) of product from 60c, 0.083 ml (0.60 mmol) of triethylamine and 0.12 g (0.36 mmol) of TBTU in 8 ml THF.

C₂₇H₄₁N₃O₅S (519.70)

[M+H]+=520

HPLC (Method 4): retention time=3.2 min

EXAMPLE 61

61a)

61a is prepared analogously to 28c from 1.00 g (6.67 mmol) of 4-chloropyridine hydrochloride (Aldrich) and 2.55 g (15.00 mmol) of N-methyl-N-piperidin-4-ylmethyl-acetamide (DE 110635, Rhône-Poulenc, 1961) in 1 ml of water.

C₁₄H₂₁N₃O (247.34)

[M+H]+=248

61b)

A mixture of 1.00 g (4.04 mmol) of product from 61a and 10 ml semiconcentrated HCl is refluxed for three days. The reaction mixture is then diluted with water, made alkaline with 20% sodium hydroxide solution and extracted with ethyl acetate. The organic extracts are dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₂H₁₉N₃ (205.30)

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.2

61c)

Example 61 is prepared analogously to 1f from 0.099 g (0.30 mmol) of product from 53c, 0.062 g (0.30 mmol) of product from 61b, 0.083 ml (0.60 mmol) of triethylamine and 0.12 g (0.36 mmol) of TBTU in 8 ml THF and 1 ml DMF.

C₂₆H₃₈N₄O₅S (518.67)

[M+H]+=519

HPLC (Method 4): retention time=3.2 min

EXAMPLE 62

62a)

A mixture of 1.69 g (10.00 mmol) of 4-(1H-imidazol-4-yl)-benzonitrile (J. Am. Chem. Soc. 93, 1971, 4256-4263), 1.12 g (10.00 mmol) of potassium-tert-butoxide and 25 ml DMSO is first stirred for 30 min at ambient temperature, then slowly combined with 0.62 ml (10.00 mmol) of methyl iodide and stirred for another 2.5 hours at ambient temperature. The reaction mixture is then added to water, the precipitate formed is filtered off and dried in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/ethanol 19:1).

C₁₁H₉N₃ (183.21)

[M+H]+=184

HPLC (Method 4): retention time=1.9 min

62b)

62b is prepared analogously to 34b from 1.02 g (5.57 mmol) of product from 62a, 0.20 g Raney nickel and 30 ml of methanolic ammonia solution.

C₁₁H₁₃N₃ (187.24)

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.27

62c)

Example 62 is prepared analogously to 1f from 0.099 g (0.30 mmol) of product from 53c, 0.056 g (0.30 mmol) of product from 62b, 0.083 ml (0.60 mmol) of triethylamine and 0.12 g (0.36 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₅H₃₂N₄O₅S×HCl (537.07)

[M+H]+=501

HPLC (Method 4): retention time=3.2 min

EXAMPLE 63

63a)

5.00 g (22.32 mmol) of 2-bromo-4′-cyano-acetophenone (Aldrich) and 10.00 g (169.29 mmol) of acetamide (Merck) are heated together with stirring for two hours to 210° C. After cooling, the reaction mixture is stirred into water and acidified with 2 M HCl. The precipitate is filtered off and discarded. The filtrate is made alkaline with concentrated ammonia solution, the precipitate is filtered off and dried in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/ethanol 9:1).

C₁₁H₉N₃ (183.21)

[M−H]-=182

HPLC (Method 4): retention time=1.9 min

63b)

63b is prepared analogously to 62a from 2.39 g (13.05 mmol) of product from 63a, 1.46 g (13.05 mmol) of potassium-tert-butoxide and 0.81 ml (13.05 mmol) of methyl iodide in 50 ml DMSO.

C₁₂H₁₁N₃ (197.24)

[M+H]+=198

HPLC (Method 4): retention time=1.9 min

63c)

63c is prepared analogously to 34b from 2.04 g (10.34 mmol) of product from 63b, 0.40 g Raney nickel and 50 ml of methanolic ammonia solution.

C₁₂H₁₅N₃ (201.27)

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.19

63d)

Example 63 is prepared analogously to 1f from 0.099 g (0.30 mmol) of product from 53c, 0.060 g (0.30 mmol) of product from 63c, 0.083 ml (0.60 mmol) of triethylamine and 0.12 g (0.36 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₆H₃₄N₄O₅S×HCl (551.10)

[M+H]+=515

HPLC (Method 4): retention time=3.2 min

EXAMPLE 64

64a)

64a is prepared analogously to 1f from 4.00 g (19.21 mmol) of ethyl 4-carboxymethyl-benzoate (J. Med. Chem. 41, 1998, 5219-5246), 19.21 ml (38.42 mmol) of dimethylamine 2 M in THF (Aldrich), 5.36 ml (38.42 mmol) of triethylamine and 7.39 g (23.00 mmol) of TBTU in 100 ml THF.

C₁₃H₁₇NO₃ (235.28)

[M+H]+=236

HPLC (Method 4): retention time=3.3 min

64b)

A mixture of 3.07 g (13.05 mmol) of product from 64a, 9.75 ml (39.00 mmol) of 4 M sodium hydroxide solution, 9.75 ml of water and 50 ml of ethanol is stirred overnight at ambient temperature. Then the ethanol is eliminated in vacuo. The aqueous residue is acidified with 4 M HCl and extracted with ethyl acetate. The organic extracts are dried on sodium sulphate and evaporated to dryness in vacuo. The product thus obtained is triturated with diethyl ether and dried.

C₁₁H₁₃NO₃ (207.23)

[M+H]+=208

HPLC (Method 4): retention time=2.3 min

64c)

64c is prepared analogously to 1f from 2.30 g (11.10 mmol) of product from 64b, 11.10 ml (22.20 mmol) of dimethylamine 2 M in THF (Aldrich), 3.09 ml (22.20 mmol) of triethylamine and 4.28 g (13.32 mmol) of TBTU in 70 ml THF.

C₁₂H₁₆N₂O₂ (220.27)

[M+H]+=221

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.44

64d)

64d is prepared analogously to 38f from 1.92 g (8.72 mmol) of product from 64c and 40.00 ml (40.00 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 150 ml THF.

C₁₂H₂₀N₂ (192.30)

[M+H]+=193

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.10

64e)

Example 64 is prepared analogously to 1f from 0.099 g (0.30 mmol) of product from 53c, 0.058 g (0.30 mmol) of product from 64d, 0.083 ml (0.60 mmol) of triethylamine and 0.12 g (0.36 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₆H₃₉N₃O₅S (505.67)

[M+H]+=508

HPLC (Method 4): retention time=3.0 min

EXAMPLE 65

65a)

65a is prepared analogously to 34b from 0.40 g (1.82 mmol) of 4-imidazo[1,2-a]pyridin-2-yl-benzonitrile (J. Med. Chem. 41, 1998, 4317-4328), 0.10 g Raney nickel and 40 ml of methanolic ammonia solution.

C₁₄H₁₃N₃ (223.27)

[M+H]+=224

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.06

65b)

A mixture of 0.40 g (1.79 mmol) of product from 65a, 0.05 g platinum oxide and 40 ml of methanol is hydrogenated at 50° C. in the autoclave. The catalyst is filtered off, the filtrate is evaporated to dryness in vacuo.

C₁₄H₁₇N₃ (227.30)

[M+H]+=228

65c)

Example 65 is prepared analogously to 1f from 0.15 g (0.44 mmol) of product from 53c, 0.10 g (0.44 mmol) of product from 65b, 0.15 ml (1.09 mmol) of triethylamine and 0.16 g (0.48 mmol) of TBTU in 30 ml THF and 10 ml DMF.

C₂₈H₃₆N₄O₅S×HCl (577.14)

[M+H]+=541

HPLC (Method 5): retention time=1.57 min

EXAMPLE 66

66a)

A mixture of 0.50 g (2.06 mmol) of 4-bromoacetylbenzoic acid (Fluorochem) and 5 ml formamide is stirred for one hour at 150° C. in the microwave. After cooling the precipitated product is filtered off, washed with diethyl ether and dried.

C₁₀H₈N₂O₂ (188.18)

[M+H]+=189

66b)

A mixture of 1.60 g (8.50 mmol) of product from 66a, 5.40 g (38.04 mmol) of methyl iodide, 7.00 g (25.33 mmol) of potassium carbonate and 30 ml DMF is stirred overnight at ambient temperature. The reaction mixture is filtered, the filtrate is evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol 100:1 to 75:1).

C₁₂H₁₂N₂O₂ (216.24)

[M+H]+=217

66c)

A mixture of 0.75 g (3.47 mmol) of product from 66b and 20 ml methylamine 33% in ethanol (Fluka) is heated to 160° C. overnight in the autoclave. The reaction mixture is evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol 50:1 to 25:1).

C₁₂H₁₃N₃O (215.25)

[M+H]+=216

66d)

66d is prepared analogously to 38f from 0.41 g (1.91 mmol) of product from 66c and 3.00 ml (3.00 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 70 ml THF.

C₁₂H₁₅N₃ (201.27)

[M+H]+=202

TLC: silica gel, dichloromethane/methanol/ammonia 8:2:0.01, Rf value=0.16

66e)

Example 66 is prepared analogously to 1f from 0.15 g (0.45 mmol) of product from 53c, 0.09 g (0.45 mmol) of product from 66d, 0.11 ml (1.09 mmol) of triethylamine and 0.16 g (0.50 mmol) of TBTU in 30 ml THF and 5 ml DMF.

C₂₆H₃₄N₄O₅S×HCl (551.10)

[M+H]+=515

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.52

EXAMPLE 67

67a)

A mixture of 1.21 g (6.14 mmol) of product from 63b, 20 ml 20% sodium hydroxide solution and 40 ml of ethanol is refluxed overnight with stirring. The ethanol is eliminated in vacuo. The residue is diluted with water and acidified with 4 M HCl. The precipitated product is filtered off and dried at 50° C. in the circulating air dryer.

C₁₂H₁₂N₂O₂ (252.70)

[M+H]+=217

HPLC (Method 4): retention time=1.7 min

67b)

67b is prepared analogously to 1f from 1.55 g (6.13 mmol) of product from 67a, 4.60 ml (9.20 mmol) of methylamine 2 M in THF (Aldrich), 1.71 ml (12.30 mmol) of triethylamine and 2.38 g (7.40 mmol) of TBTU in 50 ml THF.

C₁₃H₁₅N₃O (229.28)

[M+H]+=230

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.47

67c)

67c is prepared analogously to 38f from 1.33 g (5.80 mmol) of product from 67b and 15.00 ml (15.00 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 80 ml THF.

C₁₃H₁₇N₃ (215.29)

[M+H]+=216

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.29

67d)

Example 67 is prepared analogously to 1f from 0.099 g (0.30 mmol) of product from 53c, 0.065 g (0.30 mmol) of product from 67c, 0.083 ml (0.60 mmol) of triethylamine and 0.12 g (0.36 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₇H₃₆N₄O₅S×HCl (565.13)

[M+H]+=529

HPLC (Method 4): retention time=3.1 min

EXAMPLE 68

68a)

68a is prepared analogously to 1f from 5.39 g (20.16 mmol) of 1-benzhydryl-azetidine-3-carboxylic acid (Acros), 15 ml (30.00 mmol) of methylamine 2 M in THF (Aldrich), 5.58 ml (40.00 mmol) of triethylamine and 7.71 g (24.00 mmol) of TBTU in 150 ml THF.

C₁₈H₂₀N₂O (280.36)

HPLC (Method 4): retention time=2.5 min

68b)

A mixture of 5.32 g (18.98 mmol) of product from 68a, 0.50 g palladium on charcoal (10%) and 100 ml of methanol is hydrogenated for 24 hours at ambient temperature in the autoclave. The catalyst is filtered off, the filtrate is evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography through silica gel (eluant: dichloromethane/methanol/ammonia 70:30:3).

C₅H₁₀N₂O (114.15)

TLC: silica gel, dichloromethane/methanol/ammonia 7:3:0.3, Rf value=0.17

68c)

68c is prepared analogously to 28c from 1.31 g (8.76 mmol) of 4-chloropyridine hydrochloride (Aldrich), 1.00 g (8.76 mmol) of product from 68b and 2.40 ml (17.22 mmol) of triethylamine in 5 ml of ethanol.

C₁₀H₁₃N₃O (191.23)

[M+H]+=192

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.25

68d)

68d is prepared analogously to 38f from 0.46 g (2.41 mmol) of product from 68c and 5.00 ml (5.00 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 20 ml THF.

C₁₀H₁₅N₃ (177.25)

[M+H]+=178

TLC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.40

68e)

Example 68 is prepared analogously to 1f from 0.083 g (0.25 mmol) of product from 53c, 0.044 g (0.25 mmol) of product from 68d, 0.070 ml (0.50 mmol) of triethylamine and 0.096 g (0.30 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₄H₃₄N₄O₅S (490.62)

[M+H]+=491

HPLC (Method 4): retention time=2.9 min

EXAMPLE 69

Example 69 is prepared analogously to 1f from 0.083 g (0.25 mmol) of product from 53c, 0.041 g (0.25 mmol) of 4-(2-dimethylamino-ethyl)-phenylamine (JW Pharmlab), 0.070 ml (0.50 mmol) of triethylamine and 0.096 g (0.30 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₄H₃₅N₃O₅S×HCl (514.08)

[M+H]+=478

HPLC (Method 4): retention time=3.1 min

EXAMPLE 70

Example 70 is prepared analogously to 1f from 0.083 g (0.25 mmol) of product from 53c, 0.048 g (0.25 mmol) of 3-(2-diethylamino-ethyl)-phenylamine (analogously to J. Med. Chem. 28, 1985, 1533-1536), 0.070 ml (0.50 mmol) of triethylamine and 0.096 g (0.30 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₆H₃₉N₃O₅S (505.67)

[M+H]+=506

HPLC (Method 4): retention time=3.4 min

EXAMPLE 71

Example 71 is prepared analogously to 1f from 0.083 g (0.25 mmol) of product from 53c, 0.038 g (0.25 mmol) of 4-dimethylaminomethyl-phenylamine (J. Chem. Soc. 1935, 871), 0.070 ml (0.50 mmol) of triethylamine and 0.096 g (0.30 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₃H₃₃N₃O₅S (463.59)

[M+H]+=464

HPLC (Method 4): retention time=3.1 min

EXAMPLE 72

72a)

72a is prepared analogously to 60a from 0.82 g (5.00 mmol) of 4-formyl-benzoic acid methylamide (EMKA), 0.50 ml (5.00 mmol) of cyclopentylamine (Aldrich), 0.37 ml (6.50 mmol) of acetic acid and 1.59 g (7.50 mmol) of sodium triacetoxyborohydride in 30 ml THF.

C₁₄H₂₀N₂O (232.32)

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.15

72b)

72b is prepared analogously to 38f from 1.00 g (4.30 mmol) of product from 72a and 9.00 ml (9.00 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 40 ml THF.

C₁₄H₂₂N₂ (218.34)

[M+H]+=219

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.2

72c)

Example 72 is prepared analogously to 1f from 0.20 g (0.60 mmol) of product from 53c, 0.13 g (0.60 mmol) of product from 72b, 0.21 ml (1.50 mmol) of triethylamine and 0.23 g (0.72 mmol) of TBTU in 10 ml THF.

C₂₈H₄₁N₃O₅S×HCl (568.17)

[M+H]+=532

HPLC (Method 5): retention time=1.60 min

EXAMPLE 73

73a)

A mixture of 2.60 g (11.65 mmol) of product from 65a, 2.55 g (11.68 mmol) of Boc-anhydride and 100 ml DMF is stirred for two hours at ambient temperature. Then 100 ml of water are slowly added thereto. The precipitated product is filtered off, washed with water and petroleum ether and dried.

C₁₉H₂₁N₃O₂ (323.39)

[M+H]+=324

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.78

73b)

73b is prepared analogously to 62a from 1.00 g (3.09 mmol) of product from 73a, 0.70 g (6.24 mmol) of potassium-tert-butoxide and 0.98 ml (6.90 mmol) of methyl iodide in 30 ml DMSO.

C₁₇H₁₇N₃O₂ (295.34)

[M+H]+=296

73c)

A mixture of 0.59 g (1.75 mmol) of product from 73b, 2 ml TFA and 30 ml dichloromethane is stirred for three hours at ambient temperature. The reaction mixture is then washed with water, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₅H₁₅N₃ (237.30)

[M+H]+=238

73d)

Example 73 is prepared analogously to 1f from 0.14 g (0.42 mmol) of product from 53c, 0.10 g (0.42 mmol) of product from 73c, 0.10 ml (0.99 mmol) of triethylamine and 0.15 g (0.46 mmol) of TBTU in 30 ml THF and 5 ml DMF.

C₂₉H₃₄N₄O₅S×HCl (587.13)

[M+H]+=551

HPLC (Method 5): retention time=1.58 min

EXAMPLE 74

74a)

74a is prepared analogously to 53b from 4.08 g (14.93 mmol) of product from 53a, 4.68 g (22.39 mmol) of tert-butyl 2-bromopropionate (TCI), 1.38 g (4.98 mmol) of tetrabutylammonium chloride (Fluka) and 70 ml of 35% sodium hydroxide solution in 70 ml of toluene.

C₁₉H₃₁NO₆S (401.52)

[M+H]+=402

TLC: silica gel, petroleum ether/ethyl acetate 7:3, Rf value=0.69

74b)

74b is prepared analogously to 53c from 5.12 g (12.75 mmol) of product from 74a and 5.89 ml TFA in 80 ml dichloromethane.

C₁₅H₂₃NO₆S (345.41)

[M+H]+=346

TLC: silica gel, dichloromethane/ethanol 19:1, Rf value=0.25

74c)

Example 74 is prepared analogously to 1f from 0.10 g (0.30 mmol) of product from 74b, 0.058 g (0.30 mmol) of product from 64d, 0.084 ml (0.60 mmol) of triethylamine and 0.12 g (0.36 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₇H₄₁N₃O₅S (519.70)

[M+H]+=520

HPLC (Method 4): retention time=3.1 min

EXAMPLE 75

75a)

75a is prepared analogously to 60a from 0.82 g (5.00 mmol) of 4-formyl-benzoic acid methylamide (EMKA), 0.67 ml (5.00 mmol) of 4-methylcyclohexylamine cis/trans mixture (Acros), 0.37 ml (6.50 mmol) of acetic acid and 1.59 g (7.50 mmol) of sodium triacetoxyborohydride in 30 ml THF.

C₁₆H₂₄N₂O (260.37)

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.25

75b)

75b is prepared analogously to 38f from 1.30 g (4.99 mmol) of product from 75a and 10.00 ml (10.00 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 50 ml THF.

C₁₆H₂₆N₂ (246.39)

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.2

75c)

Example 75 is prepared analogously to 1f from 0.20 g (0.60 mmol) of product from 53c, 0.15 g (0.60 mmol) of product from 75b, 0.21 ml (1.50 mmol) of triethylamine and 0.23 g (0.72 mmol) of TBTU in 10 ml THF.

C₃₀H₄₅N₃O₅S×HCl (596.22)

[M+H]+=560

HPLC (Method 5): retention time=1.65 min

EXAMPLE 76

Example 76 is prepared analogously to 1f from 0.10 g (0.30 mmol) of product from 74b, 0.060 g (0.30 mmol) of product from 63c, 0.084 ml (0.60 mmol) of triethylamine and 0.12 g (0.36 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₇H₃₆N₄O₅S (528.66)

[M+H]+=529

HPLC (Method 4): retention time=3.2 min

EXAMPLE 77

77a)

77a is prepared analogously to 60a from 0.82 g (5.00 mmol) of 4-formyl-benzoic acid methylamide (EMKA), 0.58 ml (5.00 mmol) of 3-pentylamine (Aldrich), 0.37 ml (6.50 mmol) of acetic acid and 1.59 g (7.50 mmol) of sodium triacetoxyborohydride in 30 ml THF.

C₁₄H₂₂N₂O (234.34)

[M+H]+=235

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.4

77b)

77b is prepared analogously to 38f from 1.10 g (4.69 mmol) of product from 77a and 9.40 ml (9.40 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 40 ml THF.

C₁₄H₂₄N₂ (220.35)

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.1

77c)

Example 77 is prepared analogously to 1f from 0.20 g (0.60 mmol) of product from 53c, 0.13 g (0.60 mmol) of product from 77b, 0.21 ml (1.50 mmol) of triethylamine and 0.23 g (0.72 mmol) of TBTU in 10 ml THF.

C₂₈H₄₃N₃O₅S×HCl (570.18)

[M+H]+=534

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.45

EXAMPLE 78

78a)

78a is prepared analogously to 60a from 0.82 g (5.00 mmol) of 4-formyl-benzoic acid methylamide (EMKA), 0.53 ml (5.00 mmol) of tert-butylamine (Fluka), 0.37 ml (6.50 mmol) of acetic acid and 1.59 g (7.50 mmol) of sodium triacetoxyborohydride in 30 ml THF.

C₁₃H₂₀N₂O (220.31)

[M+H]+=221

TLC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.15

78b)

78b is prepared analogously to 38f from 1.00 g (4.54 mmol) of product from 78a and 9.10 ml (9.10 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 40 ml THF.

C₁₃H₂₂N₂ (206.33)

78c)

Example 78 is prepared analogously to 1f from 0.20 g (0.60 mmol) of product from 53c, 0.12 g (0.60 mmol) of product from 78b, 0.21 ml (1.50 mmol) of triethylamine and 0.23 g (0.72 mmol) of TBTU in 10 ml THF.

C₂₇H₄₁N₃O₅S (519.70)

[M+H]+=520

HPLC (Method 5): retention time=1.58 min

EXAMPLE 79

79a)

A mixture of 0.50 ml (4.70 mmol) of 1-fluoro-3-nitrobenzene (Fluka), 1.34 g (9.39 mmol) of 4-(N,N-dimethylaminomethyl)-piperidine (Eur. J. Med. Chem. Chim. Ther. 37, 2002, 487-502), 0.65 g (4.70 mmol) of potassium carbonate and 6.6 ml DMSO is stirred for five days at 110° C. The reaction mixture is then poured onto ice, the precipitate formed is filtered off. The product thus obtained is dried overnight in the vacuum desiccator.

C₁₄H₂₁N₃O₂ (263.34)

[M+H]+=264

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.20

79b)

A mixture of 0.95 ml (3.60 mmol) of product from 79a, 0.095 g palladium on charcoal (5%) and 72 ml of ethanol is hydrogenated at ambient temperature in the autoclave. The catalyst is filtered off, the filtrate is evaporated to dryness in vacuo.

C₁₄H₂₃N₃ (233.35)

[M+H]+=234

79c)

Example 79 is prepared analogously to 1f from 0.15 g (0.46 mmol) of product from 53c, 0.11 g (0.46 mmol) of product from 79b, 0.084 ml (0.60 mmol) of triethylamine and 0.18 g (0.56 mmol) of TBTU in 3 ml DMF.

C₂₈H₄₂N₄O₅S (546.72)

[M+H]+=547

HPLC (Method 5): retention time=1.49 min

EXAMPLE 80

80a)

80a is prepared analogously to 33a from 0.70 g (3.01 mmol) of 4-(4-dimethylamino-piperidin-1-yl)-benzaldehyde (Tetrahedron 57, 2001, 4781-4785), 3.00 ml (31.88 mmol) of methylamine 33% in ethanol (Aldrich), 0.20 g Raney nickel in 25 ml of ethanol.

C₁₅H₂₅N₃ (247.38)

[M+H]+=248

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.16

80b)

Example 80 is prepared analogously to 1f from 0.15 g (0.45 mmol) of product from 53c, 0.11 g (0.45 mmol) of product from 80a, 0.13 ml (0.90 mmol) of triethylamine and 0.17 g (0.54 mmol) of TBTU in 5 ml DMF.

C₂₉H₄₄N₄O₅S×HCl (597.21)

[M+H]+=561

HPLC (Method 1): retention time=2.33 min

EXAMPLE 81

81a)

81a is prepared analogously to 33a from 1.00 g (4.90 mmol) of 4-(4-methyl-piperazin-1-yl)-benzaldehyde (Chem. Pharm Bull. 45, 1997, 1458-1469), 4.00 ml (42.50 mmol) of methylamine 33% in ethanol (Aldrich), 0.20 g Raney nickel in 30 ml of ethanol.

C₁₃H₂₁N₃ (219.33)

[M+H]+=220

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.15

81b)

Example 81 is prepared analogously to 1f from 0.15 g (0.45 mmol) of product from 53c, 0.099 g (0.45 mmol) of product from 81a, 0.13 ml (0.90 mmol) of triethylamine and 0.17 g (0.54 mmol) of TBTU in 5 ml DMF.

C₂₇H₄₀N₄O₅S×HCl (569.16)

[M+H]+=533

HPLC (Method 1): retention time=2.28 min

EXAMPLE 82

Example 82 is prepared analogously to 1f from 0.15 g (0.45 mmol) of product from 53c, 0.092 g (0.45 mmol) of product from 19b, 0.13 ml (0.90 mmol) of triethylamine and 0.17 g (0.54 mmol) of TBTU in 5 ml DMF.

C₂₆H₃₈N₄O₅S×HCl (555.13)

[M+H]+=519

HPLC (Method 1): retention time=2.29 min

EXAMPLE 83

83a)

83a is prepared analogously to 51a from 1.35 g (5.16 mmol) of product from 41b, 1.24 g (5.68 mmol) of Boc-anhydride and 0.80 ml (5.68 mmol) of triethylamine in 50 ml dichloromethane.

C₂₁H₃₅N₃O₂ (361.52)

[M+H]+=362

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.42

83b)

83b is prepared analogously to 51b from 1.80 g (4.98 mmol) of product from 83a and 0.57 g (15.00 mmol) of lithium aluminium hydride (Aldrich) in 25 ml THF.

C₁₇H₂₉N₃ (275.43)

[M+H]+=276

HPLC (Method 1): retention time=1.77 min

83c)

Example 83 is prepared analogously to 1f from 0.14 g (0.50 mmol) of product from 22c, 0.15 g (0.50 mmol) of product from 83b, 0.14 ml (1.00 mmol) of triethylamine and 0.18 g (0.55 mmol) of TBTU in 6 ml DMF.

C₃₀H₄₆N₄O₄S×HCl (595.24)

[M+H]+=559

HPLC (Method 1): retention time=2.46 min

EXAMPLE 84

Example 84 is prepared analogously to 1f from 0.15 g (0.50 mmol) of product from 22c, 0.10 g (0.50 mmol) of 4-(1-methylpiperidin-4-yloxy)-phenylamine (ART-CHEM), 0.14 ml (1.00 mmol) of triethylamine and 0.18 g (0.55 mmol) of TBTU in 6 ml DMF.

C₂₅H₃₅N₃O₅S×HCl (526.09)

[M+H]+=490

HPLC (Method 1): retention time=2.40 min

EXAMPLE 85

Example 85 is prepared analogously to 1f from 0.15 g (0.50 mmol) of product from 22c, 0.09 g (0.50 mmol) of 4-(2-dimethylamino-ethoxy)-phenylamine (Collect. Czech. Chem. Commun. 55, 1990, 282-295), 0.14 ml (1.00 mmol) of triethylamine and 0.18 g (0.55 mmol) of TBTU in 6 ml DMF.

C₂₃H₃₃N₃O₅S×HCl (500.05)

[M+H]+=464

HPLC (Method 1): retention time=2.35 min

EXAMPLE 86

Example 86 is prepared analogously to 1f from 0.14 g (0.45 mmol) of product from 22c, 0.099 g (0.45 mmol) of product from 81a, 0.13 ml (0.90 mmol) of triethylamine and 0.17 g (0.54 mmol) of TBTU in 5 ml DMF.

C₂₆H₃₈N₄O₅S×HCl (539.13)

[M+H]+=503

HPLC (Method 1): retention time=2.43 min

EXAMPLE 87

87a)

A mixture of 0.11 g (0.33 mmol) of product from 27c, 0.043 g (0.33 mmol) of 3-amino-6-chloropyridazine (Acros), 0.12 ml (0.66 mmol) of DIPEA and 10 ml dichloromethane is refluxed for three days with stirring. The precipitate is then filtered off. The filtrate is evaporated to dryness in vacuo and the crude product is purified by preparative HPLC.

C₁₇H₂₁ClN₄O₄S (412.89)

[M+H]+=413/415

87b)

A mixture of 0.03 g (0.073 mmol) of product from 87a and 0.013 g (0.073 mmol) of diethyl-piperidin-4-ylmethyl-amine (Chem. Pharm. Bull. 42, 1994, 74-84) is melted at 173° C. The product is then recovered from the reaction mixture by preparative HPLC.

C₂₇H₄₂N₆O₄S (546.73)

[M+H]+=547

HPLC (Method 6): retention time=2.12 min

EXAMPLE 88

88a)

88a is prepared analogously to 51a from 0.70 g (3.18 mmol) of product from 27b, 0.80 g (3.65 mmol) of Boc-anhydride and 5.50 ml (11.00 mmol) of 2 M sodium hydroxide solution in 40 ml dioxane and 20 ml of water.

C₁₇H₂₈N₄O₂ (320.43)

[M+H]+=321

TLC: silica gel, dichloromethane/methanol/ammonia 4:1:0.2, Rf value=0.83

88b)

88b is prepared analogously to 51b from 0.60 g (1.87 mmol) of product from 88a and 0.21 g (5.60 mmol) of lithium aluminium hydride (Aldrich) in 20 ml THF.

C₁₃H₂₂N₄ (234.34)

[M+H]+=235

TLC: silica gel, dichloromethane/methanol/ammonia 4:1:0.2, Rf value=0.62

88c)

Example 88 is prepared analogously to 27d from 0.16 g (0.50 mmol) of product from 27c, 0.12 g (0.50 mmol) of product from 88b and 0.17 ml (1.00 mmol) of DIPEA in 5 ml THF.

C₂₆H₃₉N₅O₄S×HCl (554.15)

[M+H]+=518

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.61

EXAMPLE 89

89a)

89a is prepared analogously to 8a from 0.70 g (4.18 mmol) of 4-piperidinopiperidine (Aldrich), 0.44 ml (4.18 mmol) of 1-fluoro-4-nitrobenzene (Acros) and 1.33 ml (9.61 mmol) of triethylamine in 12 ml DMF.

C₁₆H₂₃N₃O₂ (289.37)

[M+H]+=290

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.3

89b)

89b is prepared analogously to 8b from 0.96 g (3.32 mmol) of product from 89a and 0.093 g palladium on charcoal (5%) in 45 ml of ethanol.

C₁₆H₂₅N₃ (259.39)

[M+H]+=260

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.2

89c)

Example 89 is prepared analogously to 1f from 0.10 g (0.33 mmol) of product from 22c, 0.086 g (0.33 mmol) of product from 89b, 0.14 ml (1.00 mmol) of triethylamine and 0.11 g (0.33 mmol) of TBTU in 2 ml THF.

C₂₉H₄₂N₄O₄S×C₂HF₃O₂ (656.76)

[M+H]+=543

HPLC (Method 5): retention time=1.47 min

EXAMPLE 90

90a)

90a is prepared analogously to 8a from 0.84 g (4.18 mmol) of 4-N-Boc-aminopiperidine (Acros), 0.44 ml (4.18 mmol) of 1-fluoro-4-nitrobenzene (Acros) and 1.33 ml (9.61 mmol) of triethylamine in 12 ml DMF.

C₁₆H₂₃N₃O₄ (321.37)

[M+H]+=322

90b)

90b is prepared analogously to 8b from 1.01 g (3.43 mmol) of product from 90a and 0.11 g palladium on charcoal (5%) in 45 ml of ethanol.

C₁₆H₂₅N₃O₂ (291.39)

[M+H]+=292

90c)

90c is prepared analogously to 1f from 0.10 g (0.33 mmol) of product from 22c, 0.097 g (0.33 mmol) of product from 90b, 0.14 ml (1.00 mmol) of triethylamine and 0.11 g (0.33 mmol) of TBTU in 2 ml THF.

C₂₉H₄₂N₄O₆S (574.73)

[M+H]+=575

HPLC (Method 5): retention time=1.62 min

90d)

Example 90 is prepared analogously to 18b from 0.19 g (0.33 mmol) of product from 90c and 0.33 ml TFA in 0.5 ml dichloromethane.

C₂₄H₃₄N₄O₄S×C₂HF₃O₂ (588.64)

[M+H]+=475

HPLC (Method 5): retention time=1.41 min

EXAMPLE 91

91a)

91a is prepared analogously to 8a from 0.90 g (4.18 mmol) of tert-butyl methyl-piperidin-4-yl-carbamate (Fluorochem), 0.44 ml (4.18 mmol) of 1-fluoro-4-nitrobenzene (Acros) and 1.33 ml (9.61 mmol) of triethylamine in 12 ml DMF.

C₁₇H₂₅N₃O₄ (335.40)

[M+H]+=336

TLC: silica gel, dichloromethane/methanol 30:1, Rf value=0.6

91b)

91b is prepared analogously to 8b from 1.08 g (3.22 mmol) of product from 91a and 0.11 g palladium on charcoal (5%) in 45 ml of ethanol.

C₁₇H₂₇N₃O₂ (305.42)

[M+H]+=306

TLC: silica gel, dichloromethane/methanol 30:1, Rf value=0.4

91c)

91c is prepared analogously to 1f from 0.10 g (0.33 mmol) of product from 22c, 0.10 g (0.33 mmol) of product from 91b, 0.14 ml (1.00 mmol) of triethylamine and 0.11 g (0.33 mmol) of TBTU in 2 ml THF.

C₃₀H₄₄N₄O₆S (588.76)

[M+H]+=589

HPLC (Method 5): retention time=1.69 min

91d)

Example 91 is prepared analogously to 18b from 0.21 g (0.36 mmol) of product from 91c and 0.36 ml TFA in 0.6 ml dichloromethane.

C₂₅H₃₆N₄O₄S×C₂HF₃O₂ (602.67)

[M+H]+=489

HPLC (Method 5): retention time=1.42 min

EXAMPLE 92

92a)

A mixture of 0.66 g (5.16 mmol) of 4-dimethylamino-piperidine (Alfa Aesar), 1.00 g (4.69 mmol) of tert-butyl (4-oxocyclohexyl)-carbamate (Fluorochem), 1.19 g (5.16 mmol) of sodium triacetoxyborohydride and 20 ml dichloromethane is stirred under nitrogen for four hours at ambient temperature. The reaction mixture is then diluted with dichloromethane, washed with saturated sodium hydrogen carbonate solution, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₈H₃₅N₃O₂ (325.49)

92b)

A mixture of 0.80 g (2.46 mmol) of product from 92a, 4 ml 6 M HCl, 3 ml 37% HCl and 3 ml of methanol is stirred for two hours at 50° C. The reaction mixture is then evaporated to dryness in vacuo.

C₁₃H₂₇N₃×3HCl (334.76)

92c)

Example 92 is prepared analogously to 1f from 0.10 g (0.33 mmol) of product from 22c, 0.13 g (0.40 mmol) of product from 92b, 0.23 ml (1.66 mmol) of triethylamine and 0.13 g (0.40 mmol) of TBTU in 8 ml DMF.

C₂₆H₄₄N₄O₄S×2HCl (581.64)

[M+H]+=509

HPLC (Method 5): retention time=1.36 min

EXAMPLE 93

93a)

93a is carried out analogously to 92a from 0.63 g (3.70 mmol) of diethyl-piperidin-4-ylmethyl-amine (Chem. Pharm. Bull. 42, 1994, 74-84), 0.72 g (3.37 mmol) of tert-butyl (4-oxocyclohexyl)-carbamate (Fluorochem) and 0.86 g (4.04 mmol) of sodium triacetoxyborohydride in 20 ml dichloromethane.

C₂₁H₄₁N₃O₂ (367.57)

93b)

93b is prepared analogously to 92b from 0.90 g (2.45 mmol) of product from 93a, 4 ml 6 M HCl and 3 ml 37% HCl in 3 ml of methanol.

C₁₆H₃₃N₃×3HCl (376.84)

93c)

Example 93 is prepared analogously to 1f from 0.10 g (0.33 mmol) of product from 22c, 0.14 g (0.37 mmol) of product from 93b, 0.23 ml (1.66 mmol) of triethylamine and 0.13 g (0.40 mmol) of TBTU in 8 ml DMF.

C₂₉H₅₀N₄O₄S×2HCl (623.72)

[M+H]+=551

HPLC (Method 5): retention time=1.39 min

EXAMPLE 94

94a)

A mixture of 0.88 g (6.88 mmol) of 4-dimethylamino-piperidine (Alfa Aesar), 1.00 g (4.93 mmol) of 3-bromo-6-nitropyridine (Aldrich), 0.18 g (0.49 mmol) of tetrabutyl-ammonium iodide, 0.74 g (5.33 mmol) of potassium carbonate and 5 ml DMSO is stirred for two hours at 80° C. Then the reaction mixture is poured onto water and extracted with dichloromethane. The organic extracts are washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo. The crude product thus obtained is purified by preparative HPLC.

C₁₂H₁₈N₄O₂×CH₂O₂ (296.32)

HPLC (Method 1): retention time=1.49 min

94b)

94b is prepared analogously to 8b from 0.50 g (2.00 mmol) of product from 94a and 0.08 g palladium on charcoal (10%) in 40 ml of methanol.

C₁₂H₂₀N₄ (220.31)

94c)

A mixture of 0.63 g (2.10 mmol) of product from 22c, 0.91 g (9.00 mmol) of N-methylmorpholine, 0.45 g (2.04 mmol) of product from 94b and 50 ml THF is stirred for 10 minutes at ambient temperature and then combined with 5.22 ml (9.00 mmol) of propylphosphonic anhydride 50% in ethyl acetate (Fluka). The reaction mixture is stirred overnight at ambient temperature and then evaporated to dryness in vacuo. The residue is combined with 2 N potassium carbonate solution and extracted with dichloromethane. The organic extracts are washed with water and saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo. The crude product thus obtained is purified by preparative HPLC.

C₂₅H₃₇N₅O₄S×C₂HF₃O₂ (617.68)

[M+H]+=504

HPLC (Method 5): retention time=1.38 min

EXAMPLE 95

Example 95 is prepared analogously to 1f from 0.08 g (0.27 mmol) of product from 22c, 0.066 g (0.27 mmol) of product from 80a, 0.11 ml (0.80 mmol) of triethylamine and 0.085 g (0.27 mmol) of TBTU in 2 ml THF.

C₂₈H₄₂N₄O₄S×C₂HF₃O₂ (644.75)

[M+H]+=531

HPLC (Method 5): retention time=1.50 min

EXAMPLE 96

Example 96 is prepared analogously to 1f from 0.08 g (0.27 mmol) of product from 22c, 0.054 g (0.27 mmol) of product from 19b, 0.11 ml (0.80 mmol) of triethylamine and 0.085 g (0.27 mmol) of TBTU in 2 ml THF.

C₂₅H₃₆N₄O₄S×C₂HF₃O₂ (602.67)

[M+H]+=489

HPLC (Method 5): retention time=1.49 min

EXAMPLE 97

97a)

97a is prepared analogously to 8a from 1.00 g (5.87 mmol) of diethyl-piperidin-4-ylmethyl-amine (Chem. Pharm. Bull. 42, 1994, 74-84), 0.91 g (5.87 mmol) of 1-fluoro-2-methyl-4-nitrobenzene (ABCR) and 1.14 ml (8.20 mmol) of triethylamine in 12 ml DMF.

C₁₇H₂₇N₃O₂ (305.42)

[M+H]+=306

97b)

97b is prepared analogously to 8b from 0.91 g (2.98 mmol) of product from 97a and 0.20 g palladium on charcoal (10%) in 50 ml of methanol.

C₁₇H₂₉N₃ (275.43)

97c)

Example 97 is prepared analogously to 1f from 0.15 g (0.50 mmol) of product from 22c, 0.14 g (0.50 mmol) of product from 97b, 0.21 ml (1.50 mmol) of triethylamine and 0.16 g (0.50 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₃₀H₄₆N₄O₄S×HCl (595.24)

[M+H]+=559

HPLC (Method 5): retention time=1.44 min

EXAMPLE 98

98a)

98a is prepared analogously to 8a from 0.75 g (5.87 mmol) of 4-dimethylamino-piperidine (Alfar Aesar), 0.91 g (5.87 mmol) of 1-fluoro-2-methyl-4-nitrobenzene (ABCR) and 1.14 ml (8.20 mmol) of triethylamine in 12 ml DMF.

C₁₄H₂₁N₃O₂ (263.34)

98b)

98b is prepared analogously to 8b from 0.30 g (1.14 mmol) of product from 98a and 0.10 g palladium on charcoal (10%) in 25 ml of methanol.

C₁₄H₂₃N₃ (233.35)

98r)

Example 98 is prepared analogously to 1f from 0.32 g (1.07 mmol) of product from 22c, 0.25 g (1.07 mmol) of product from 98b, 0.42 ml (3.00 mmol) of triethylamine and 0.34 g (1.07 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₇H₄₀N₄O₄S×HCl (553.16)

[M+H]+=517

HPLC (Method 5): retention time=1.52 min

EXAMPLE 99

99a)

99a is prepared analogously to 8a from 0.92 g (5.87 mmol) of dimethyl-(2-piperidin-4-yl-ethyl)-amine (J. Med. Chem. 36, 1993, 162-165), 0.91 g (5.87 mmol) of 1-fluoro-2-methyl-4-nitrobenzene (ABCR) and 2.49 g (18.00 mmol) of potassium carbonate in 12 ml DMF.

C₁₆H₂₅N₃O₂ (291.39)

[M+H]+=292

99b)

99b is prepared analogously to 8b from 0.60 g (1.14 mmol) of product from 99a and 0.20 g palladium on charcoal (10%) in 50 ml of methanol.

C₁₆H₂₇N₃ (261.41)

99c)

Example 99 is prepared analogously to 1f from 0.15 g (0.50 mmol) of product from 22c, 0.13 g (0.50 mmol) of product from 99b, 0.21 ml (1.50 mmol) of triethylamine and 0.16 g (0.50 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₉H₄₄N₄O₄S×HCl (581.21)

[M+H]+=545

HPLC (Method 5): retention time=1.42 min

EXAMPLE 100

100a)

100a is prepared analogously to 8a from 1.00 g (4.47 mmol) of 4-(3-methyl-3H-imidazol-4-yl)-piperidine (J. Med. Chem. 46, 2003, 5445-5457), 0.63 g (4.47 mmol) of 4-fluoro-nitrobenzene (ABCR) and 2.10 g (15.20 mmol) of potassium carbonate in 50 ml DMF.

C₁₄H₁₆N₄O₂ (272.30)

[M+H]+=273

100b)

10b-1 and 100b-2 are prepared analogously to 62a from 1.10 g (4.04 mmol) of product from 100a, 0.60 g (4.23 mmol) of methyl iodide and 0.46 g (4.10 mmol) of potassium-tert-butoxide in 50 ml DMSO. The resulting mixture of isomers is separated by column chromatography through silica gel (eluant: dichloromethane/methanol 100:1 to 30:1).

100b-1: C₁₅H₁₈N₄O₂ (286.33)

[M+H]+=287

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.50

100b-2: C₁₅H₁₈N₄O₂ (286.33)

[M+H]+=287

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.38

100c)

100c is prepared analogously to 8b from 0.10 g (0.35 mmol) of 100b-2 and 0.20 g palladium on charcoal (10%) in 30 ml of methanol.

C₁₅H₂₀N₄ (256.35)

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.10

Example 100 is prepared analogously to 1f from 0.085 g (0.28 mmol) of product from 22c, 0.070 g (0.27 mmol) of product from 100c, 0.048 ml (0.35 mmol) of triethylamine and 0.095 g (0.30 mmol) of TBTU in 20 ml THF and 3 ml DMF.

C₂₈H₃₇N₅O₄S×HCl (576.15)

[M+H]+=540

HPLC (Method 5): retention time=1.41 min

EXAMPLE 101

101a)

101a is prepared analogously to 8b from 0.35 g (1.22 mmol) of 100b-1 and 0.50 g palladium on charcoal (10%) in 50 ml of methanol.

C₁₅H₂₀N₄ (256.35)

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.14

101b)

Example 101 is prepared analogously to 1f from 0.12 g (0.40 mmol) of product from 22c, 0.10 g (0.39 mmol) of product from 101a, 0.05 ml (0.50 mmol) of triethylamine and 0.14 g (0.42 mmol) of TBTU in 30 ml THF and 5 ml DMF.

C₂₈H₃₇N₅O₄S (539.69)

[M+H]+=540

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.47

EXAMPLE 102

102a)

102a is prepared analogously to 60a from 0.50 g (5.00 mmol) of N-methylcyclohexylamine (CHESS), 0.82 g (5.00 mmol) of 4-formyl-benzoic acid methylamide (EMKA), 1.59 g (7.50 mmol) of sodium triacetoxyborohydride and 0.37 ml (6.50 mmol) of acetic acid in 30 ml THF.

C₁₅H₂₂N₂ (246.35)

102b)

102b is prepared analogously to 38f from 1.06 g (4.30 mmol) of product from 102a and 8.60 ml (8.60 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 40 ml THF.

C₁₅H₂₄N₂ (232.36)

102c)

Example 102 is prepared analogously to 1f from 0.20 g (0.60 mmol) of product from 53c, 0.14 g (0.60 mmol) of product from 102b, 0.21 ml (1.50 mmol) of triethylamine and 0.23 g (0.72 mmol) of TBTU in 10 ml THF.

C₂₉H₄₃N₃O₅S×HCl (582.20)

[M+H]+=546

HPLC (Method 5): retention time=1.58 min

EXAMPLE 103

103a)

A mixture of 0.04 g (0.079 mmol) of 70, 4.8 mg (0.12 mmol) of sodium hydride 60%, 1 ml THF and 0.5 ml DMF is stirred for 30 minutes at ambient temperature. Then 4.9 μl (0.079 mmol) of methyl iodide are added and the mixture is stirred for a further two hours at ambient temperature. The reaction mixture is then evaporated to dryness in vacuo, the residue is mixed with water and extracted with ethyl acetate. The organic extracts are dried on sodium sulphate and evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography (eluant: dichloromethane/methanol/ammonia 95:5:0.5).

C₁₃H₂₂N₂ (206.33)

[M+H]+=207

103b)

Example 103 is prepared analogously to 1f from 0.08 g (0.24 mmol) of product from 53c, 0.05 g (0.24 mmol) of product from 103a, 0.067 ml (0.48 mmol) of triethylamine and 0.093 g (0.29 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₇H₄₁N₃O₅S (519.70)

[M+H]+=520

HPLC (Method 4): retention time=3.2 min

EXAMPLE 104

104a)

104a is prepared analogously to 60a from 0.35 g (1.72 mmol) of 4-(2-methyl-1.3-thiazol-4-yl)-benzaldehyde (Maybridge), 1.50 ml (3.00 mmol) of methylamine 2 M in THF (Acros), 0.70 g (3.30 mmol) of sodium triacetoxyborohydride and 0.23 ml (4.00 mmol) of acetic acid in 20 ml THF.

C₁₂H₁₄N₂S (218.32)

[M+H]+=219

104b)

Example 104 is prepared analogously to 1f from 0.16 g (0.47 mmol) of product from 53c, 0.10 g (0.46 mmol) of product from 104a, 0.11 ml (1.09 mmol) of triethylamine and 0.16 g (0.48 mmol) of TBTU in 30 ml THF and 5 ml DMF.

C₂₆H₃₃N₃O₅S₂ (531.69)

[M+H]+=532

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.66

EXAMPLE 105

Example 105 is prepared analogously to 1f from 0.14 g (0.41 mmol) of product from 53c, 0.10 g (0.40 mmol) of methyl-[3-(2-morpholin-4-yl-ethoxy)-benzyl]-amine (Maybridge), 0.14 ml (0.99 mmol) of triethylamine and 0.14 g (0.44 mmol) of TBTU in 30 ml THF and 5 ml DMF.

C₂₈H₄₁N₃O₇S×HCl (600.17)

[M+H]+=564

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.59

EXAMPLE 106

Example 106 is prepared analogously to 1f from 0.17 g (0.51 mmol) of product from 53c, 0.10 g (0.50 mmol) of methyl-(3-pyrimidin-5-yl-benzyl)-amine (Maybridge), 0.17 ml (1.19 mmol) of triethylamine and 0.17 g (0.53 mmol) of TBTU in 30 ml THF and 5 ml DMF.

C₂₆H₃₂N₄O₅S×HCl (549.08)

[M+H]+=513

HPLC (Method 5): retention time=1.78 min

EXAMPLE 107

Example 107 is prepared analogously to 1f from 0.18 g (0.54 mmol) of product from 53c, 0.10 g (0.53 mmol) of (4-furan-2-yl-benzyl)-methyl-amine (Maybridge), 0.18 ml (1.29 mmol) of triethylamine and 0.18 g (0.56 mmol) of TBTU in 30 ml THF and 5 ml DMF.

C₂₆H₃₂N₂O₆S (500.61)

[M+H]+=501

HPLC (Method 5): retention time=2.09 min

EXAMPLE 108

108a)

107a is prepared analogously to 79a from 2.41 g (18.78 mmol) of 4-dimethylamino-piperidine (Alfa Aesar), 1.00 ml (9.39 mmol) of 1-fluoro-3-nitrobenzene (Fluka) and 1.30 g (9.39 mmol) of potassium carbonate in 15 ml DMSO.

C₁₃H₁₉N₃O₂ (249.31)

[M+H]+=250

108b)

A mixture of 1.74 g (6.98 mmol) of product from 108a, 12.00 g (68.92 mmol) of sodium dithionite, 10.00 g (72.35 mmol) of potassium carbonate, 60 ml THF and 30 ml of water six hours is heated to 80° C. After cooling the organic phase is separated off, washed with saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₃H₂₁N₃ (219.33)

108c)

Example 108 is prepared analogously to 1f from 0.13 g (0.40 mmol) of product from 53c, 0.10 g (0.47 mmol) of product from 108b, 0.067 ml (0.48 mmol) of triethylamine and 0.15 g (0.48 mmol) of TBTU in 5 ml DMF.

C₂₇H₄₀N₄O₅S (532.70)

[M+H]+=533

HPLC (Method 5): retention time=1.56 min

EXAMPLE 109

109a)

A mixture of 0.59 g (3.12 mmol) of 4-pyrrolidin-1-ylmethyl-benzylamine (Enamine-BB), 0.29 ml (3.75 mmol) of methyl chloroformate (Fluka), 0.52 ml (3.75 mmol) of triethylamine and 10 ml dichloromethane is stirred for two hours at ambient temperature. The reaction mixture is diluted with 10 ml dichloromethane, washed twice with water, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₄H₂₀N₂O₂ (248.32)

109b)

109b is prepared analogously to 51b from 0.61 g (2.44 mmol) of product from 109a and 5.00 ml (5.00 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 5 ml THF.

C₁₃H₂₀N₂ (204.31)

109c)

Example 109 is prepared analogously to 1f from 0.18 g (0.54 mmol) of product from 53c, 0.17 g (0.81 mmol) of product from 109b, 0.15 ml (1.07 mmol) of triethylamine and 0.21 g (0.65 mmol) of TBTU in 4 ml DMF.

C₂₇H₃₉N₃O₅S×CH₂O₂ (631.71)

[M+H]+=518

HPLC (Method 5): retention time=1.56 min

EXAMPLE 110

Example 110 is prepared analogously to 1f from 0.12 g (0.36 mmol) of product from 53c, 0.096 g (0.51 mmol) of 4-pyrrolidin-1-ylmethyl-benzylamine (Enamine-BB), 0.10 ml (0.72 mmol) of triethylamine and 0.14 g (0.44 mmol) of TBTU in 4 ml DMF.

C₂₆H₃₇N₃O₅S×CH₂O₂ (617.68)

[M+H]+=504

HPLC (Method 5): retention time=1.56 min

EXAMPLE 111

111a)

A mixture of 1.00 g (4.25 mmol) of tert-butyl (4-formylbenzyl)-carbamate (Acros) and 10 ml dichloromethane is combined successively with 1.15 ml (8.50 mmol) of cis-2,6-dimethylpiperidine (Aldrich) and 1.80 g (8.50 mmol) of sodium triacetoxyborohydride while cooling with an ice bath. The reaction mixture is stirred for three days at ambient temperature, then slowly quenched with saturated sodium hydrogen carbonate solution and extracted with dichloromethane. The organic extracts are washed with water and saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography (eluant: dichloromethane/methanol 93:7).

C₂₀H₃₂N₂O₂ (332.48)

[M+H]+=333

HPLC (Method 5): retention time=1.47 min

111b)

111b is prepared analogously to 51b from 0.92 g (2.76 mmol) of product from 111a and 8.27 ml (8.27 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 30 ml THF.

C₁₆H₂₆N₂ (246.39)

[M+H]+=247

HPLC (Method 5): retention time=1.03 min

Example 111 is prepared analogously to 1f from 0.08 g (0.24 mmol) of product from 53c, 0.059 g (0.24 mmol) of product from 111b, 0.10 ml (0.72 mmol) of triethylamine and 0.078 g (0.24 mmol) of TBTU in 2 ml THF.

C₃₀H₄₅N₃O₅S×C₂HF₃O₂ (673.78)

[M+H]+=560

HPLC (Method 5): retention time=1.59 min

EXAMPLE 112

112a)

250.00 ml (500.00 mmol) of methylamine 2 M in methanol (Fluka) are slowly combined with 54.00 g (250.00 mmol) of 4-nitrobenzylbromide (Fluka) while cooling with an ice bath. The reaction mixture is stirred for one hour while cooling with an ice bath and for 30 minutes at ambient temperature and then evaporated to dryness in vacuo. The residue is stirred with diethyl ether and filtered off. The filtrate is evaporated to dryness in vacuo, combined with sodium carbonate solution and extracted with diethyl ether. The organic extracts are dried on sodium sulphate and evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography (eluant: dichloromethane/methanol 5:0 to 5:1).

C₈H₁₀N₂O₂ (166.18)

[M+H]+=167

112b)

A mixture of 13.40 g (80.64 mmol) of product from 112a and 25 ml ethyl acetate is slowly combined with 17.68 g (81.00 mmol) of Boc-anhydride while cooling with an ice bath. The reaction mixture is stirred for three hours at ambient temperature, then washed with water, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₃H₁₈N₂O₄ (266.29)

112c)

A mixture of 23.00 g (86.37 mmol) of product from 112b, 2.30 g Raney nickel, 230 ml of ethanol and 230 ml ethyl acetate is hydrogenated in the autoclave at ambient temperature. The catalyst is filtered off, the filtrate is evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography (eluant: petroleum ether/ethyl acetate 1:1).

C₁₃H₂₀N₂O₂ (236.31)

[M+H]+=237

TLC: silica gel, petroleum ether/ethyl acetate 1:1, Rf value=0.55

112d)

A mixture of 0.50 g (2.12 mmol) of product from 112c, 0.48 g (3.56 mmol) of trimethylsilyl isocyanate (Fluka) and 15 ml THF is refluxed over the weekend with stirring. Then the reaction mixture is evaporated to dryness in vacuo.

C₁₄H₂₁N₃O₃ (279.33)

[2M+H]+=559

112e)

A mixture of 0.64 g (2.29 mmol) of product from 112d and 10 ml of methanolic HCl is stirred for three hours at ambient temperature and for two hours at 50° C. Then the reaction mixture is evaporated to dryness in vacuo. The residue is dried overnight in vacuo.

C₉H₁₃N₃×HCl (215.68)

[M+H]+=180

112f)

Example 112 is prepared analogously to 1f from 0.20 g (0.60 mmol) of product from 53c, 0.13 g (0.60 mmol) of product from 112e, 0.42 ml (3.02 mmol) of triethylamine and 0.22 g (0.66 mmol) of TBTU in 4 ml DMF.

C₂₃H₃₂N₄O₆S (492.59)

[M+H]+=493

HPLC (Method 6): retention time=2.93 min

EXAMPLE 113

113a)

A mixture of 2.00 g (9.92 mmol) of 4-methylaminomethyl-benzoic acid hydrochloride (J. Med. Chem. 26, 1983, 309-312) and 25 ml of ethanolic HCl is stirred for 1.5 hours at reflux temperature. Then the reaction mixture is evaporated to dryness in vacuo.

C₁₁H₁₅NO₂×HCl (229.70)

[M+H]+=194

HPLC (Method 6): retention time=1.39 min

113b)

113b is prepared analogously to 1f from 0.70 g (2.11 mmol) of product from 53c, 0.49 g (2.11 mmol) of product from 113a, 0.88 ml (6.34 mmol) of triethylamine and 0.78 g (2.32 mmol) of TBTU in 12 ml DMF.

C₂₅H₃₄N₂O₇S (506.61)

[M+H]+=507

HPLC (Method 6): retention time=3.95 min

113c)

A mixture of 1.06 g (2.09 mmol) of product from 133b, 7.00 ml (7.00 mmol) of 1 M sodium hydroxide solution, 15 ml THF and 1.5 ml of ethanol is stirred for four hours at 50° C. The reaction mixture is then combined with 7 ml 1 M HCl and evaporated to dryness in vacuo. The residue is taken up in acetone, dried on magnesium sulphate and evaporated to dryness in vacuo.

C₂₃H₃₀N₂O₇S (478.56)

[M+H]+=479

HPLC (Method 6): retention time=3.21 min

113d)

Example 113 is prepared analogously to 1f from 0.50 g (1.05 mmol) of product from 113c, 4.00 ml (2.00 mmol) of ammonia 0.5 M in dioxane, 0.44 ml (3.14 mmol) of triethylamine and 0.38 g (1.15 mmol) of TBTU in 4 ml DMF.

C₂₃H₃₁N₃O₆S (477.57)

[M+H]+=478

HPLC (Method 6): retention time=2.92 min

EXAMPLE 114

A mixture of 0.075 g (0.15 mmol) of 61, 0.1 g (0.71 mmol) of methyl iodide and 5 ml dichloromethane is stirred overnight at ambient temperature. The reaction mixture is then evaporated to dryness in vacuo.

C₂₇H₄₁N₄O₅S×I (660.61)

[M+H]+=533

HPLC (Method 5): retention time=1.55 min

EXAMPLE 115

Example 115 is prepared analogously to 114 from 0.03 g (0.059 mmol) of 64 and 0.05 g (0.35 mmol) of methyl iodide in 5 ml dichloromethane.

C₂₇H₄₂N₃O₅S×I (647.61)

[M+H]+=520

HPLC (Method 5): retention time=1.55 min

EXAMPLE 116

116a)

116a is prepared analogously to 1f from 0.50 g (1.05 mmol) of product from 113c, 0.14 g (1.05 mmol) of tert-butyl hydrazine carboxylate (Aldrich), 0.58 ml (4.18 mmol) of triethylamine and 0.38 g (1.15 mmol) of TBTU in 6 ml DMF.

C₂₈H₄₀N₄O₈S (592.71)

[M+H]+=593

HPLC (Method 6): retention time=3.46 min

116b)

Example 116 is prepared analogously to 112e from 0.68 g (1.15 mmol) of product from 116a and 10 ml of methanolic HCl.

C₂₃H₃₂N₄O₆S×C₂HF₃O₂ (606.61)

[M+H]+=493

HPLC (Method 6): retention time=3.46 min

EXAMPLE 117

117a)

A mixture of 3.20 g (17.47 mmol) of product from 63a, 50 ml 20% sodium hydroxide solution and 50 ml of ethanol is refluxed overnight with stirring. Then the ethanol is eliminated in vacuo and the aqueous residue is neutralised with concentrated HCl. The precipitate formed is filtered off and dried.

C₁₁H₁₀N₂O₂ (202.21)

[M+H]+=203

117b)

A mixture of 2.70 g (13.35 mmol) of product from 117a, 8.00 g (57.89 mmol) of potassium carbonate and 100 ml DMF is stirred for one hour at 60° C. After cooling the reaction mixture is combined with 3.50 g (27.65 mmol) of benzyl chloride (Aldrich) at ambient temperature and then stirred over the weekend at 60° C. The reaction mixture is poured onto water and stirred for one hour at ambient temperature. The precipitate formed is filtered off and dried.

C₂₅H₂₂N₂O₂ (382.45)

[M+H]+=383

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.64

117c)

A mixture of 1.80 g (4.71 mmol) of product from 117b and 100 ml methylamine 33% in ethanol (Aldrich) is stirred for six hours at 180° C. and overnight at 160° C. in the autoclave. The reaction mixture is then evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography (eluant: dichloromethane/methanol 19:1).

C₁₉H₁₉N₃O (305.37)

[M+H]+=306

117d)

A mixture of 1.20 g (3.93 mmol) of product from 117c, 0.20 g palladium on charcoal (20%) and 50 ml of methanol is hydrogenated at 50° C. in the autoclave. The catalyst is filtered off, the filtrate is evaporated to dryness in vacuo.

C₁₂H₁₃N₃O (215.25)

[M+H]+=216

117e)

117e is prepared analogously to 38f from 0.70 g (3.25 mmol) of product from 117d and 10.00 ml (10.00 mmol) of lithium aluminium hydride 1 M in THF (Aldrich) in 200 ml THF.

C₁₂H₁₅N₃ (201.27)

[M+H]+=202

117f)

Example 117 is prepared analogously to 1f from 0.17 g (0.51 mmol) of product from 53c, 0.10 g (0.50 mmol) of product from 117e, 0.17 ml (1.19 mmol) of triethylamine and 0.17 g (0.53 mmol) of TBTU in 30 ml THF and 5 ml DMF.

C₂₆H₃₄N₄O₅S (514.64)

[M+H]+=515

TLC: silica gel, dichloromethane/methanol 9:1, Rf value=0.28

EXAMPLE 118

118a)

118a is prepared analogously to 13a from 0.75 g (4.05 mmol) of 5-bromo-m-xylene (Aldrich), 0.55 ml (8.30 mmol) of chlorosulphonic acid (Aldrich) and 10 ml dichloromethane.

C₈H₈BrClO₂S (283.57)

HPLC (Method 6): retention time=4.76 min

118b)

118b is prepared analogously to 3a from 0.65 g (2.29 mmol) of product from 118a and 0.28 ml (3.44 mmol) of N-methylaminoethanol (BASF) in 5 ml THF.

C₁₁H₁₆BrNO₃S (322.22)

HPLC (Method 6): retention time=3.38 min

118c)

118c is first prepared analogously to 53b from 0.74 g (2.29 mmol) of product from 118b, 0.75 g (5.06 mmol) of tert-butyl 2-bromopropionate (Fluka), 0.42 g (1.14 mmol) of tetrabutylammonium iodide (Aldrich) and 8.67 g (75.90 mmol) of 35% sodium hydroxide solution in 40 ml of toluene. The tert-butyl ester is then stirred overnight together with 2 ml HCl 4 M in dioxane (Aldrich) in 4 ml dioxane at ambient temperature. The product is then obtained by evaporating the reaction mixture in vacuo.

C₁₃H₁₈BrNO₅S (380.26)

HPLC (Method 6): retention time=3.48 min

118d)

Example 118 is prepared analogously to 1f from 0.10 g (0.26 mmol) of product from 118c, 0.054 g (0.26 mmol) of product from 61b, 0.11 ml (0.79 mmol) of triethylamine and 0.084 g (0.26 mmol) of TBTU in 10 ml THF and 3 ml DMF.

C₂₅H₃₅BrN₄O₄S (567.54)

[M+H]+=568/569/571

HPLC (Method 6): retention time=2.77 min

EXAMPLE 119

A mixture of 0.03 g (0.053 mmol) of 118 and 0.03 g palladium on charcoal in 5 ml of methanol is hydrogenated in the autoclave at ambient temperature. The catalyst is filtered off, the filtrate is evaporated to dryness in vacuo. The crude product thus obtained is purified by preparative HPLC.

C₂₅H₃₆N₄O₄S (488.64)

[M+H]+=489

HPLC (Method 6): retention time=2.45 min

EXAMPLE 120

120a)

120a is prepared analogously to 3a from 0.50 g (2.29 mmol) of 2,4,6-trimethylbenzene-sulphonic acid chloride (Fluka) and 0.19 g (2.52 mmol) of N-methylaminoethanol (BASF) in 5 ml THF.

C₁₂H₁₉NO₃S (257.35)

[M+H]+=258

120b)

120b is prepared analogously to 118c from 0.56 g (2.18 mmol) of product from 120a, 0.48 ml (3.26 mmol) of tert-butyl 2-bromopropionate (Fluka), 0.18 g (0.65 mmol) of tetrabutylammonium chloride (Fluka) and 7.46 g (65.28 mmol) of 35% sodium hydroxide solution in 20 ml of toluene and subsequent stirring in 2 ml HCl 4 M in dioxane.

C₁₄H₂₁NO₅S (315.39)

120c)

Example 120 is prepared analogously to 1f from 0.10 g (0.32 mmol) of product from 120b, 0.065 g (0.32 mmol) of product from 61b, 0.13 ml (0.95 mmol) of triethylamine and 0.20 g (0.63 mmol) of TBTU in 10 ml THF.

C₂₆H₃₈N₄O₄S (502.67)

[M+H]+=503

HPLC (Method 5): retention time=1.57 min

EXAMPLE 121

121a)

A mixture of 0.98 g (7.05 mmol) of sarcosine methylester hydrochloride (Fluka), 1.65 g (7.05 mmol) of product from 13a and 50 ml of pyridine is stirred for one hour at ambient temperature. The reaction mixture is then evaporated to dryness in vacuo. The residue is then taken up in 1 M HCl and extracted with ethyl acetate. The organic extracts are dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₃H₁₉NO₅S (301.36)

[M+H]+=302

121b)

A mixture of 1.90 g (6.29 mmol) of product from 121a, 6.45 ml (12.90 mmol) of 2 M sodium hydroxide solution and 9 ml of methanol is stirred for three days at ambient temperature. The methanol is eliminated in vacuo, the aqueous residue is poured onto 1 M HCl. The precipitate formed is filtered off and dried overnight in the vacuum desiccator.

C₁₂H₁₇NO₅S (287.33)

[M+H]+=288

121c)

121c is prepared analogously to 1f from 0.20 g (0.70 mmol) of product from 121b, 0.087 g (0.70 mmol) of glycine methylester hydrochloride (Aldrich), 0.29 ml (2.09 mmol) of triethylamine and 0.22 g (0.70 mmol) of TBTU in 5 ml THF.

C₁₅H₂₂N₂O₆S (358.41)

[M+H]+=359

HPLC (Method 5): retention time=1.72 min

121d)

121d is prepared analogously to 121b from 0.23 g (0.63 mmol) of product from 121c and 0.64 ml (1.29 mmol) of 2 M sodium hydroxide solution in 1 ml of methanol.

C₁₄H₂₀N₂O₆S (344.38)

[M+H]+=345

121e)

121e is prepared analogously to 28c from 3.00 g (14.00 mmol) of tert-butyl piperidine-4-ylmethyl-carbamate (EMKA), 2.10 g (14.00 mmol) of 4-chloropyridine hydrochloride (Aldrich) and 7.80 ml (56.32 mmol) of triethylamine in 15 ml isopropanol.

C₁₆H₂₅N₃O₂ (291.39)

[M+H]+=292

HPLC (Method 5): retention time=1.40 min

121f)

121f is prepared analogously to 18b from 1.44 g (4.95 mmol) of product from 121e and 4.95 ml TFA in 8 ml dichloromethane.

C₁₁H₁₇N₃×2C₂HF₃O₂ (419.32)

[M+H]+=192

HPLC (Method 5): retention time=0.36 min

121g)

Example 121 is prepared analogously to 1f from 0.09 g (0.26 mmol) of product from 121d, 0.11 g (0.26 mmol) of product from 121f, 0.15 ml (1.05 mmol) of triethylamine and 0.084 g (0.26 mmol) of TBTU in 1.9 ml THF.

C₂₅H₃₅N₅O₅S×C₂HF₃O₂ (631.67)

[M+H]+=518

HPLC (Method 5): retention time=1.46 min

EXAMPLE 122

Example 122 is prepared analogously to 1f from 0.09 g (0.26 mmol) of product from 121d, 0.054 g (0.26 mmol) of product from 61b, 0.11 ml (0.78 mmol) of triethylamine and 0.084 g (0.26 mmol) of TBTU in 1.9 ml THF.

C₂₆H₃₇N₅O₅S×C₂HF₃O₂ (645.69)

[M+H]+=532

HPLC (Method 5): retention time=1.50 min

EXAMPLE 123

123a)

123a is prepared analogously to 1f from 0.20 g (0.70 mmol) of product from 121b, 0.097 g (0.70 mmol) of sarcosine methylester hydrochloride (Fluka), 0.29 ml (2.09 mmol) of triethylamine and 0.22 g (0.70 mmol) of TBTU in 5 ml THF.

C₁₆H₂₄N₂O₆S (372.44)

[M+H]+=373

HPLC (Method 5): retention time=1.78 min

123b)

123b is prepared analogously to 121b from 0.23 g (0.60 mmol) of product from 123a and 0.62 ml (1.24 mmol) of 2 M sodium hydroxide solution in 1 ml of methanol.

C₁₅H₂₂N₂O₆S (258.41)

[M+H]+=359

123c)

Example 123 is prepared analogously to 1f from 0.094 g (0.26 mmol) of product from 123b, 0.11 g (0.26 mmol) of product from 121f, 0.15 ml (1.05 mmol) of triethylamine and 0.084 g (0.26 mmol) of TBTU in 1.9 ml THF.

C₂₆H₃₇N₅O₅S×C₂HF₃O₂ (645.69)

[M+H]+=532

HPLC (Method 5): retention time=1.47 min

EXAMPLE 124

Example 124 is prepared analogously to 1f from 0.094 g (0.26 mmol) of product from 123b, 0.054 g (0.26 mmol) of product from 61b, 0.11 ml (0.78 mmol) of triethylamine and 0.084 g (0.26 mmol) of TBTU in 1.9 ml THF.

C₂₇H₃₉N₅O₅S×C₂HF₃O₂ (659.72)

[M+H]+=548

HPLC (Method 5): retention time=1.49 min

EXAMPLE 125

Example 125 is prepared analogously to 1f from 0.09 g (0.26 mmol) of product from 121d, 0.076 g (0.26 mmol) of product from 54b, 0.11 ml (0.78 mmol) of triethylamine and 0.084 g (0.26 mmol) of TBTU in 1.9 ml THF.

C₂₇H₃₈N₄O₅S (530.68)

[M+H]+=531

HPLC (Method 1): retention time=2.43 min

EXAMPLE 126

Example 126 is prepared analogously to 1f from 0.09 g (0.26 mmol) of product from 121d, 0.05 g (0.26 mmol) of product from 59b, 0.11 ml (0.78 mmol) of triethylamine and 0.084 g (0.26 mmol) of TBTU in 1.9 ml THF.

C₂₆H₃₈N₄O₅S×HCl (555.13)

[M+H]+=519

HPLC (Method 1): retention time=2.42 min

EXAMPLE 127

Example 127 is prepared analogously to 1f from 0.09 g (0.26 mmol) of product from 121d, 0.065 g (0.26 mmol) of product from 80a, 0.11 ml (0.78 mmol) of triethylamine and 0.084 g (0.26 mmol) of TBTU in 1.9 ml THF.

C₂₉H₄₃N₅O₅S×HCl (610.21)

[M+H]+=574

HPLC (Method 1): retention time=2.38 min

EXAMPLE 128

Example 128 is prepared analogously to 1f from 0.09 g (0.26 mmol) of product from 121d, 0.057 g (0.26 mmol) of product from 81a, 0.11 ml (0.78 mmol) of triethylamine and 0.084 g (0.26 mmol) of TBTU in 1.9 ml THF.

C₂₇H₃₉N₅O₅S×C₂HF₃O₂ (610.21)

[M+H]+=546

HPLC (Method 5): retention time=1.51 min

EXAMPLE 129

Example 129 is prepared analogously to 1f from 0.09 g (0.26 mmol) of product from 121d, 0.056 g (0.26 mmol) of product from 67c, 0.11 ml (0.78 mmol) of triethylamine and 0.084 g (0.26 mmol) of TBTU in 1.9 ml THF.

C₂₇H₃₅N₅O₅S×C₂HF₃O₂ (655.69)

[M+H]+=542

HPLC (Method 5): retention time=1.52 min

EXAMPLE 130

130a)

130a is prepared analogously to 10d from 0.50 g (2.13 mmol) of product from 13a, 0.42 g (2.13 mmol) of ethyl 5-methylaminovalerate (J. Am. Chem. Soc. 55, 1933, 1233-1241) and 1.18 ml (8.52 mmol) of triethylamine in 15 ml THF.

C₁₇H₂₇NO₅S (357.47)

[M+H]+=358

HPLC (Method 6): retention time=4.10 min

130b)

130b is prepared analogously to 121b from 0.62 g (1.73 mmol) of product from 130a and 7.00 ml (7.00 mmol) of 1 M sodium hydroxide solution in 1.5 ml of methanol and 15 ml THF.

C₁₅H₂₃NO₅S (329.41)

[M+H]+=330

HPLC (Method 6): retention time=3.24 min

130c)

Example 130 is prepared analogously to 1f from 0.18 g (0.54 mmol) of product from 130b, 0.10 g (0.49 mmol) of product from 61b, 0.14 ml (0.97 mmol) of triethylamine and 0.18 g (0.54 mmol) of TBTU in 3 ml DMF.

C₂₇H₄₀N₄O₄S (516.70)

[M+H]+=517

HPLC (Method 6): retention time=2.65 min

EXAMPLE 131

Example 131 is prepared analogously to 1f from 0.069 g (0.21 mmol) of product from 130b, 0.088 g (0.21 mmol) of product from 121f, 0.087 ml (0.63 mmol) of triethylamine and 0.077 g (0.23 mmol) of TBTU in 1 ml DMF.

C₂₆H₃₈N₄O₄S×CH₂O₂ (548.71)

[M+H]+=503

HPLC (Method 6): retention time=2.52 min

EXAMPLE 132

132a)

A mixture of 2.50 g (9.15 mmol) of product from 53a, 1.39 ml (10.00 mmol) of triethylamine and 50 ml THF is combined at ambient temperature with 0.77 ml (10.00 mmol) of methanesulphonic acid chloride (Aldrich). The reaction mixture is then stirred overnight at ambient temperature. The precipitate formed is filtered off. The filtrate is evaporated to dryness in vacuo. The residue is taken up in ethyl acetate and washed with water and saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₃H₂₁NO₆S₂ (351.44)

[M+H]+=352

TLC: silica gel, dichloromethane/methanol 9.5:0.5, Rf value=0.95

132b)

A mixture of 0.50 g (1.42 mmol) of product from 132a, 0.20 g (1.42 mmol) of sarcosine methylester hydrochloride (Aldrich), 0.52 ml (3.00 mmol) of DIPEA and 5 ml DMF is stirred for 24 hours at 80° C. The reaction mixture is evaporated down in vacuo. The residue is taken up in dichloromethane and washed with water and saturated sodium hydrogen carbonate solution, dried on sodium sulphate and evaporated to dryness in vacuo. The crude product thus obtained is purified by column chromatography (eluant: dichloromethane/0-3% methanol).

C₁₆H₂₆N₂O₅S (358.45)

[M+H]+=359

132c)

132c is prepared analogously to 1c from 0.29 g (0.81 mmol) of product from 132b and 0.17 g (4.00 mmol) of lithium hydroxide monohydrate (Aldrich) in 5 ml THF and 4 ml of water.

C₁₅H₂₄N₂O₅S (344.43)

HPLC (Method 1): retention time=2.32 min

132d)

Example 132 is prepared analogously to 1f from 0.10 g (0.29 mmol) of product from 132c, 0.06 g (0.29 mmol) of product from 61b, 0.084 ml (0.60 mmol) of triethylamine and 0.096 g (0.30 mmol) of TBTU in 10 ml DMF.

C₂₇H₄₁N₅O₄S×2HCl (604.63)

[M+H]+=532

HPLC (Method 5): retention time=1.39 min

EXAMPLE 133

Example 133 is prepared analogously to 1f from 0.10 g (0.29 mmol) of product from 132c, 0.12 g (0.29 mmol) of product from 121f, 0.17 ml (1.20 mmol) of triethylamine and 0.096 g (0.30 mmol) of TBTU in 60 ml DMF.

C₂₆H₃₉N₅O₄S×2HCl (590.61)

[M+H]+=518

HPLC (Method 5): retention time=1.37 min

EXAMPLE 134

134a)

A mixture of 1.60 g (4.55 mmol) of product from 132a, 2.10 g (14.00 mmol) of sodium iodide and 30 ml acetone is stirred for eight hours at reflux temperature. The reaction mixture is then filtered through silica gel. The filtrate is evaporated to dryness in vacuo. The residue is taken up in ethyl acetate, washed with water, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₂H₁₈INO₃S (383.25)

[M+H]+=384

HPLC (Method 1): retention time=3.75 min

134b)

134b is prepared analogously to 132b from 1.30 g (3.39 mmol) of product from 134a, 1.28 g (10.20 mmol) of glycine methylester hydrochloride (Aldrich) and 3.48 ml (20.00 mmol) of DIPEA in 15 ml acetonitrile.

C₁₅H₂₄N₂O₅S (344.43)

[M+H]+=345

TLC: silica gel, dichloromethane/methanol 9.5:0.5, Rf value=0.38

134c)

A mixture of 0.46 g (1.34 mmol) of product from 134b, 0.33 g (1.50 mmol) of Boc-anhydride, 0.21 ml (1.50 mmol) of triethylamine and 30 ml dichloromethane is stirred overnight at ambient temperature. The reaction mixture is then diluted with dichloromethane and washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo.

C₂₀H₃₂N₂O₇S (444.54)

[M+H]+=445

TLC: silica gel, dichloromethane/methanol 9.5:0.5, Rf value=0.45

134d)

134d is prepared analogously to 1c from 0.59 g (1.33 mmol) of product from 134c and 0.28 g (6.60 mmol) of lithium hydroxide monohydrate (Aldrich) in 7 ml THF and 6.6 ml of water.

C₁₉H₃₀N₂O₇S (430.52)

[M+H]+=431

134e)

134e is prepared analogously to 1f from 0.15 g (0.35 mmol) of product from 134d, 0.072 g (0.35 mmol) of product from 61b, 0.098 ml (0.70 mmol) of triethylamine and 0.11 g (0.35 mmol) of TBTU in 7 ml DMF.

C₃₁H₄₇N₅O₆S (617.80)

[M+H]+=618

HPLC (Method 1): retention time=2.62 min

134f)

Example 134 is prepared analogously to 18b from 0.16 g (0.26 mmol) of product from 134e and 3 ml TFA in 3 ml dichloromethane.

C₂₆H₃₉N₅O₄S×2HCl (590.61)

[M+H]+=518

HPLC (Method 5): retention time=1.40 min

EXAMPLE 135

135a)

135a is prepared analogously to 1f from 0.15 g (0.35 mmol) of product from 134d, 0.15 g (0.35 mmol) of product from 121f, 0.20 ml (1.40 mmol) of triethylamine and 0.11 g (0.35 mmol) of TBTU in 7 ml DMF.

C₃₀H₄₅N₅O₆S (603.77)

[M+H]+=604

TLC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.48

135b)

Example 135 is prepared analogously to 18b from 0.16 g (0.27 mmol) of product from 135a and 5 ml TFA in 5 ml dichloromethane.

C₂₅H₃₇N₅O₄S×2HCl (576.58)

[M+H]+=504

HPLC (Method 1): retention time=2.17 min

EXAMPLE 136

136a)

A mixture of 0.21 g (0.60 mmol) of product from 132a, 0.065 ml (0.60 mmol) of ethyl mercaptoacetate (Aldrich), 0.17 g (1.20 mmol) of potassium carbonate and 10 ml acetonitrile is stirred for 24 hours at ambient temperature. The precipitate is filtered off, the filtrate is evaporated down in vacuo. The crude product thus obtained is purified by preparative HPLC.

C₁₆H₂₅NO₅S₂ (375.51)

[M+H]+=376

136b)

136b is prepared analogously to 121b from 0.070 g (0.19 mmol) of product from 136a and 2.00 ml (2.00 mmol) of 1 M sodium hydroxide solution in 5 ml THF.

C₁₄H₂₁NO₅S₂ (347.45)

[M+H]+=348

136c)

Example 136 is prepared analogously to 1f from 0.064 g (0.18 mmol) of product from 136b, 0.038 g (0.18 mmol) of product from 61b, 0.079 ml (0.46 mmol) of DIPEA and 0.059 g (0.18 mmol) of TBTU in 5 ml DMF.

C₂₆H₃₈N₄O₄S₂ (534.74)

[M+H]+=535

HPLC (Method 6): retention time=2.68 min

EXAMPLE 137

Example 137 is prepared analogously to 1f from 0.073 g (0.21 mmol) of product from 136b, 0.088 g (0.21 mmol) of product from 121f, 0.11 ml (0.63 mmol) of DIPEA and 0.087 g (0.27 mmol) of TBTU in 5 ml DMF.

C₂₅H₃₆N₄O₄S₂×C₂HF₃O₂ (634.73)

[M+H]+=521

HPLC (Method 6): retention time=2.57 min

EXAMPLE 138

138a)

138a is prepared analogously to 3a from 2.0 g (8.52 mmol) of product of 13a, 1.37 μg (8.55 mmol) of N-Boc-ethylenediamine (Fluka) and 1.0 g (9.89 mmol) of triethylamine in 50 ml THF.

C₁₆H₂₆N₂O₅S (358.45)

[M−H]-=357

HPLC (Method 6): retention time=3.63 min

138b)

138b is prepared analogously to 3b from 3.38 g (9.43 mmol) of the product of 138a, 0.53 ml (8.55 mmol) of methyl iodide, 1.77 g (12.83 mmol) of potassium carbonate under anhydrous conditions in 30 ml DMSO.

C₁₇H₂₈N₂O₅S (372.48)

[M+H]+=373

HPLC (Method 6): retention time=3.89 min

138c)

138b is prepared analogously to 28d from 3.61 g (9.69 mmol) of the product of 138b and 10 ml TFA in 50 ml dichloromethane.

C₁₂₇H₂₀N₂O₃S (272.36)

[M+H]+=273

HPLC (Method 6): retention time=1.95 min

138d)

A mixture of 0.50 g (1.84 mmol) of the product of 138c, 0.56 ml (5.51 mmol) of triethylamine and 25 ml dichloromethane is combined with 0.38 ml (2.75 mmol) of monoethyl oxalate chloride (Fluka) in 5 ml dichloromethane while cooling with an ice bath and the mixture is stirred for two hours at ambient temperature. The reaction mixture is then diluted with dichloromethane, washed with 10% aqueous citric acid solution, saturated sodium sulphate solution and with water, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₆H₂₄N₂O₆S (372.44)

[M+H]+=373

138e)

A mixture of 0.60 g (1.60 mmol) of the product of 138d, 5.6 ml 1 M sodium hydroxide solution and 6 ml of ethanol is stirred for four hours at ambient temperature and then evaporated to dryness in vacuo. The residue is combined with 8 ml 1 M hydrochloric acid and extracted with ethyl acetate. The combined organic extracts are washed with water and saturated sodium chloride solution, dried on sodium sulphate and evaporated to dryness in vacuo.

C₁₄H₂₀N₂O₆S (344.38)

[M+H]+=345

138f)

Example 138 is prepared analogously to 1f from 40.0 mg (0.12 mmol) of the product of 138e, 48.2 mg (0.12 mmol) of N,N-dimethyl-N′-(4-methylaminomethyl-phenyl)-ethan-1,2-diamine (analogously to J. Chem. Soc 1960, 3163-3165), 0.038 ml (0.29 mmol) of DIPEA and 38.9 mg (0.12 mmol) of TBTU in 1.5 ml DMF.

C₂₆H₃₉N₅O₅S (533.68)

[M+H]+=534

HPLC (Method 6): retention time=1.61 min

EXAMPLE 139

Example 139 is prepared analogously to 1f from 40.0 mg (0.12 mmol) of the product of 138e, 22.5 mg (0.12 mmol) of N-(4-aminomethyl-phenyl)-N′,N′-dimethylethan-1,2-diamine (analogously to J. Chem. Soc 1960, 3163-3165), 0.038 ml (0.29 mmol) of DIPEA and 38.9 mg (0.12 mmol) of TBTU in 1.5 ml DMF.

C₂₅H₃₇N₅O₅S (519.66)

[M+H]+=520

HPLC (Method 6): retention time=1.53 min

The following compounds were prepared analogously to Example 22:

EXAMPLE 140

C₂₇H₃₃N₅O₄S×C₂HF₃O₂ (637.67)

[M+H]+=524

HPLC (Method 6): retention time=2.43 min

EXAMPLE 141

C₂₉H₂₉N₃O₄S×C₂HF₃O₂ (629.65)

[M+H]+=516

HPLC (Method 6): retention time=3.39 min

EXAMPLE 142

C₂₈H₃₅N₅O₄S (537.67)

[M+H]+=538

HPLC (Method 6): retention time=2.45 min

EXAMPLE 143

C₃₁H₄₄N₆O₄S×C₂HF₃O₂ (710.81)

[M+H]+=597

HPLC (Method 6): retention time=2.30 min

EXAMPLE 144

C₂₃H₂₇N₅O₅S×C₂HF₃O₂ (599.58)

[M+H]+=486

HPLC (Method 6): retention time=2.46 min

EXAMPLE 145

C₂₆H₃₉N₃O₄S (489.67)

[M+H]+=490

HPLC (Method 6): retention time=2.66 min

EXAMPLE 146

C₃₄H₃₉N₅O₄S (613.77)

[M+H]+=614

HPLC (Method 6): retention time=3.07 min

EXAMPLE 147

C₂₆H₃₉N₃O₄S×C₂HF₃O₂ (603.70)

[M+H]+=490

HPLC (Method 6): retention time=2.60 min

EXAMPLE 148

C₂₄H₃₄N₄O₅S×CH₂O₂ (536.64)

[M+H]+=491

HPLC (Method 6): retention time=2.29 min

EXAMPLE 149

C₂₅H₃₆N₄O₅S×CH₂O₂ (550.67)

[M+H]+=505

HPLC (Method 6): retention time=2.32 min

EXAMPLE 150

C₂₅H₃₆N₄O₅S (504.64)

[M+H]+=505

HPLC (Method 6): retention time=2.31 min

EXAMPLE 151

C₂₆H₃₈N₄O₅S×CH₂O₂ (564.70)

[M+H]+=519

HPLC (Method 6): retention time=2.34 min

EXAMPLE 152

C₂₇H₄₁N₅O₄S×2C₂HF₃O₂ (759.76)

[M+H]+=532

HPLC (Method 5): retention time=1.40 min

EXAMPLE 153

C₃₀H₄₆N₄O₅S×HCl (611.24)

[M+H]+=575

HPLC (Method 1): retention time=2.12 min

EXAMPLE 154

C₂₉H₄₄N₄O₅S×HCl (597.21)

[M+H]+=561

HPLC (Method 8): retention time=3.12 min

EXAMPLE 155

C₂₇H₄₀N₄O₅S×HCl (569.16)

[M+H]+=533

HPLC (Method 11): retention time=1.67 min

EXAMPLE 156

C₂₅H₃₅N₃O₄S×HCl (510.09)

[M+H]+=474

HPLC (Method 7): retention time=1.90 min

EXAMPLE 157

C₂₄H₃₃N₃O₄S×C₂HF₃O₂ (573.63)

[M+H]+=460

HPLC (Method 5): retention time=1.52 min

EXAMPLE 158

C₂₆H₃₅N₃O₄S×C₂HF₃O₂ (599.66)

[M+H]+=486

HPLC (Method 5): retention time=1.55 min

EXAMPLE 159

C₂₆H₃₇N₃O₄S×C₂HF₃O₂ (601.68)

[M+H]+=488

HPLC (Method 5): retention time=1.54 min

EXAMPLE 160

C₂₅H₃₅N₃O₅S×C₂HF₃O₂ (603.65)

[M+H]+=490

HPLC (Method 5): retention time=1.54 min

EXAMPLE 161

C₂₆H₄₀N₄O₄S×HCl (541.15)

[M+H]+=505

HPLC (Method 5): retention time=1.59 min

EXAMPLE 162

C₂₅H₃₈N₄O₄S×HCl (527.12)

[M+H]+=491

HPLC (Method 5): retention time=1.55 min

EXAMPLE 163

C₂₅H₃₇N₃O₄S×HCl (512.11)

[M+H]+=476

HPLC (Method 5): retention time=1.56 min

EXAMPLE 164

C₂₆H₃₇N₃O₄S×HCl (524.12)

[M+H]+=488

HPLC (Method 5): retention time=1.54 min

EXAMPLE 165

C₂₄H₃₆N₄O₄S×HCl (513.09)

[M+H]+=477

HPLC (Method 7): retention time=1.88 min

EXAMPLE 166

C₂₅H₃₈N₄O₄S×HCl (527.12)

[M+H]+=491

HPLC (Method 7): retention time=1.92 min

EXAMPLE 167

C₂₃H₃₄N₄O₄S×HCl (499.07)

[M+H]+=463

HPLC (Method 7): retention time=1.79 min

EXAMPLE 168

C₂₄H₃₆N₄O₄S×HCl (513.09)

[M+H]+=477

HPLC (Method 7): retention time=1.86 min

EXAMPLE 169

C₂₄H₃₄N₄O₄S×C₂HF₃O₂ (588.64)

[M+H]+=475

HPLC (Method 5): retention time=1.39 min

EXAMPLE 170

C₂₉H₄₅N₅O₄S×2HCl (632.69)

[M+H]+=560

DC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.22

EXAMPLE 171

C₂₆H₃₉N₅O₄S×2HCl (590.61)

[M+H]+=518

DC: silica gel, dichloromethane/ethanol 4:1, Rf value=0.68

EXAMPLE 172

C₂₈H₄₃N₅O₄S×2HCl (618.66)

[M+H]+=546

HPLC (Method 5): retention time=1.26 min

EXAMPLE 173

C₂₉H₄₂N₄O₄S (542.73)

[M+H]+=543

HPLC (Method 4): retention time=2.8 min

EXAMPLE 174

C₂₇H₄₁N₅O₄S×2HCl (604.63)

[M+H]+=532

HPLC (Method 5): retention time=1.39 min

EXAMPLE 175

C₂₆H₃₇FN₄O₄S×HCl (557.12)

[M+H]+=521

DC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.25

EXAMPLE 176

C₂₉H₄₃FN₄O₄S×HCl (599.20)

[M+H]+=563

DC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.40

EXAMPLE 177

C₂₈H₄₁FN₄O₄S×HCl (585.17)

[M+H]+=549

DC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.35

EXAMPLE 178

C₂₇H₄₀N₄O₄S (516.70)

[M+H]+=517

DC: silica gel, dichloromethane/ethanol/ammonia 8:2:0.01, Rf value=0.41

EXAMPLE 179

C₂₉H₄₂N₄O₄S×HCl (579.19)

[M+H]+=543

DC: silica gel, dichloromethane/ethanol/ammonia 8:2:0.01, Rf value=0.47

EXAMPLE 180

C₂₆H₃₇ClN₄O₄S×HCl (573.58)

[M+H]+=537/539

DC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.26

EXAMPLE 181

C₂₉H₄₃ClN₄O₄S×HCl (615.66)

[M+H]+=579/581

DC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.45

EXAMPLE 182

C₂₈H₄₁ClN₄O₄S×HCl (601.63)

[M+H]+=565/567

DC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.30

EXAMPLE 183

C₂₇H₃₉FN₄O₄S×HCl (571.15)

[M+H]+=535

DC: silica gel, dichloromethane/ethanol/ammonia 8:2:0.01, Rf value=0.26

EXAMPLE 184

C₂₇H₃₉BrN₄O₄S×HCl (632.05)

[M+H]+=595/597

DC: silica gel, dichloromethane/ethanol/ammonia 8:2:0.01, Rf value=0.51

EXAMPLE 185

C₃₀H₄₄N₄O₄S×HCl (593.22)

[M+H]+=557

DC: silica gel, dichloromethane/ethanol/ammonia 8:2:0.01, Rf value=0.63

EXAMPLE 186

C₂₇H₃₉ClN₄O₄S×HCl (587.60)

[M+H]+=551

DC: silica gel, dichloromethane/ethanol/ammonia 8:2:0.01, Rf value=0.58

EXAMPLE 187

C₃₀H₃₇N₅O₄S×HCl (600.17)

[M+H]+=564

HPLC (Method 4): retention time=3.0 min

EXAMPLE 188

C₂₉H₄₁ClN₄O₄S×HCl (613.64)

[M+H]+=577/579

DC: silica gel, dichloromethane/methanol 9:1, Rf value=0.24

EXAMPLE 189

C₂₆H₃₃N₅O₄S₂ (543.70)

[M+H]+=544

HPLC (Method 6): retention time=3.11 min

EXAMPLE 190

C₂₆H₃₈N₄O₅S (518.67)

[M+H]+=519

HPLC (Method 6): retention time=2.44 min

EXAMPLE 191

C₁₉H₂₅N₃O₄S×C₂HF₃O₂ (505.51)

[M+H]+=392

HPLC (Method 6): retention time=2.04 min

EXAMPLE 192

C₂₇H₃₅N₅O₅S (541.66)

[M+H]+=542

HPLC (Method 6): retention time=2.51 min

EXAMPLE 193

C₂₅H₃₆N₄O₅S (504.64)

[M+H]+=505

HPLC (Method 6): retention time=2.43 min

EXAMPLE 194

C₂₉H₃₆N₄O₄S (536.69)

[M+H]+=537

HPLC (Method 6): retention time=2.19 min

EXAMPLE 195

C₂₈H₃₈N₆O₄S (554.71)

[M+H]+=555

HPLC (Method 6): retention time=2.37 min

EXAMPLE 196

C₂₆H₃₈N₄O₄S (502.67)

[M+H]+=503

HPLC (Method 6): retention time=2.35 min

EXAMPLE 197

C₂₆H₃₈N₄O₄S (502.67)

[M+H]+=503

HPLC (Method 6): retention time=2.00 min

EXAMPLE 198

C₂₇H₃₈N₄O₅S×C₂HF₃O₂ (644.70)

[M+H]+=531

HPLC (Method 6): retention time=2.45 min

EXAMPLE 199

C₂₇H₃₈N₄O₅S (530.68)

[M+H]+=531

HPLC (Method 6): retention time=2.53 min

EXAMPLE 200

C₂₅H₃₅N₅O₄S (501.64)

[M+H]+=502

HPLC (Method 6): retention time=2.05 min

EXAMPLE 201

C₂₄H₃₁N₅O₄S (485.60)

[M+H]+=486

HPLC (Method 6): retention time=2.41 min

EXAMPLE 202

C₂₄H₃₅FN₄O₄S×CH₂O₂ (540.65)

[M+H]+=495

HPLC (Method 6): retention time=2.50 min

EXAMPLE 203

C₂₇H₃₈N₄O₅S (530.68)

[M+H]+=531

HPLC (Method 6): retention time=2.36 min

EXAMPLE 204

C₂₈H₄₂N₄O₄S (530.72)

[M+H]+=531

HPLC (Method 6): retention time=2.60 min

EXAMPLE 205

C₂₈H₄₀N₄O₅S (544.71)

[M+H]+=545

HPLC (Method 6): retention time=2.21 min

EXAMPLE 206

C₂₇H₃₉ClN₄O₄S (551.14)

[M+H]+=551/553

HPLC (Method 6): retention time=2.65 min

EXAMPLE 207

C₂₇H₄₀N₄O₄S×C₂HF₃O₂ (630.72)

[M+H]+=517

HPLC (Method 6): retention time=2.51 min

EXAMPLE 208

C₂₇H₃₈N₄O₅S×CH₂O₂ (576.71)

[M+H]+=531

HPLC (Method 6): retention time=2.33 min

EXAMPLE 209

C₂₈H₄₄N₆O₄S×C₂HF₃O₂ (674.78)

[M+H]+=561

HPLC (Method 6): retention time=2.14 min

EXAMPLE 210

C₂₈H₄₄N₆O₄S×C₂HF₃O₂ (674.78)

[M+H]+=561

HPLC (Method 6): retention time=2.43 min

EXAMPLE 211

C₂₅H₃₈N₆O₄S×C₂HF₃O₂ (632.70)

[M+H]+=519

HPLC (Method 6): retention time=2.11 min

EXAMPLE 212

C₃₀H₄₃N₃O₄S×C₂HF₃O₂ (655.77)

[M+H]+=542

HPLC (Method 6): retention time=2.75 min

EXAMPLE 213

C₂₅H₃₈N₆O₄S×C₂HF₃O₂ (632.70)

[M+H]+=519

HPLC (Method 6): retention time=2.30 min

EXAMPLE 214

C₂₇H₄₂N₆O₄S×C₂HF₃O₂ (660.75)

[M+H]+=547

HPLC (Method 6): retention time=2.08 min

EXAMPLE 215

C₂₇H₄₂N₆O₄S×C₂HF₃O₂ (660.75)

[M+H]+=547

HPLC (Method 6): retention time=2.34 min

EXAMPLE 216

C₂₈H₄₀ClN₅O₄S×CH₂O₂ (624.19)

[M+H]+=578/580

HPLC (Method 6): retention time=2.64 min

EXAMPLE 217

C₂₈H₄₁N₅O₄S×CH₂O₂ (589.75)

[M+H]+=544

HPLC (Method 6): retention time=2.09 min

EXAMPLE 218

C₂₇H₃₈N₆O₄S×CH₂O₂ (588.72)

[M+H]+=543

HPLC (Method 9): retention time=1.67 min

EXAMPLE 219

C₂₈H₄₀N₆O₄S (556.72)

[M+H]+=557

HPLC (Method 9): retention time=1.71 min

EXAMPLE 220

C₂₆H₃₆N₆O₄S×CH₂O₂ (574.69)

[M+H]+=529

HPLC (Method 9): retention time=1.61 min

EXAMPLE 221

C₂₆H₄₄N₄O₄S (508.72)

[M+H]+=509

HPLC (Method 9): retention time=1.23 min

EXAMPLE 222

C₂₇H₄₆N₄O₄S×2C₂HF₃O₂ (750.79)

[M+H]+=523

HPLC (Method 9): retention time=1.30 min

EXAMPLE 223

C₂₈H₄₈N₄O₄S×2C₂HF₃O₂ (764.82)

[M+H]+=537

HPLC (Method 9): retention time=1.31 min

EXAMPLE 224

C₂₆H₄₃N₃O₄S (493.70)

[M+H]+=494

HPLC (Method 9): retention time=1.72 min

EXAMPLE 225

C₂₄H₄₁N₃O₄S×C₂HF₃O₂ (581.69)

[M+H]+=468

HPLC (Method 9): retention time=1.69 min

EXAMPLE 226

C₂₅H₃₆N₄O₄S×C₂HF₃O₂ (602.67)

[M+H]+=489

HPLC (Method 5): retention time=1.39 min

EXAMPLE 227

C₂₉H₃₈N₅O₄S×I (679.61)

[M+H]+=552

HPLC (Method 5): retention time=1.55 min

EXAMPLE 228

C₂₉H₅₀N₄O₄S (550.80)

[M+H]+=551

HPLC (Method 5): retention time=1.38 min

EXAMPLE 229

C₂₉H₅₀N₄O₄S (550.80)

[M+H]+=551

HPLC (Method 5): retention time=1.40 min

EXAMPLE 230

C₂₈H₄₀N₄O₄S×2HCl (601.63)

[M+H]+=529

HPLC (Method 5): retention time=1.41 min

EXAMPLE 231

C₂₉H₄₃N₅O₄S (557.75)

[M+H]+=558

HPLC (Method 1): retention time=1.90 min

EXAMPLE 232

C₂₉H₄₉N₅O₄S (563.80)

[M+H]+=564

HPLC (Method 5): retention time=1.33 min

EXAMPLE 233

C₂₇H₄₇N₅O₄S×2HCl (610.68)

[M+H]+=538

HPLC (Method 7): retention time=1.74 min

EXAMPLE 234

C₂₇H₃₈N₄O₄S (610.68)

[M+H]+=515

HPLC (Method 5): retention time=1.41 min

EXAMPLE 235

C₂₉H₄₃N₅O₄S (557.75)

[M+H]+=558

HPLC (Method 5): retention time=1.43 min

EXAMPLE 236

C₂₈H₄₀N₄O₄S×2C₂HF₃O₂ (756.75)

[M+H]+=529

HPLC (Method 5): retention time=1.42 min

EXAMPLE 237

C₂₈H₄₈N₄O₄S×2HCl (609.69)

[M+H]+=537

HPLC (Method 7): retention time=1.70 min

EXAMPLE 238

C₂₆H₃₈N₄O₄S×2C₂HF₃O₂ (730.72)

[M+H]+=503

HPLC (Method 5): retention time=1.40 min

EXAMPLE 239

C₂₆H₄₄N₄O₄S×2HCl (581.64)

[M+H]+=509

HPLC (Method 5): retention time=1.38 min

EXAMPLE 240

C₂₆H₄₄N₄O₄S×2HCl (581.64)

[M+H]+=509

HPLC (Method 5): retention time=1.40 min

EXAMPLE 241

C₂₇H₄₆N₄O₄S×2HCl (595.67)

[M+H]+=523

DC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.13

EXAMPLE 242

C₂₇H₄₆N₄O₄S×2HCl (595.67)

[M+H]+=523

DC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.13

EXAMPLE 243

C₂₈H₄₆N₄O₄S×2HCl (607.68)

[M+H]+=535

HPLC (Method 5): retention time=1.10 min

EXAMPLE 244

C₂₇H₄₆N₄O₄S×2HCl (595.67)

[M+H]+=523

DC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.25

EXAMPLE 245

C₂₇H₄₆N₄O₄S×2HCl (595.67)

[M+H]+=523

DC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.25

EXAMPLE 246

C₂₇H₄₆N₄O₄S×2C₂HF₃O₂ (750.79)

[M+H]+=523

HPLC (Method 5): retention time=1.38 min

EXAMPLE 247

C₂₉H₄₈N₄O₄S×2C₂HF₃O₂ (776.83)

[M+H]+=549

HPLC (Method 5): retention time=1.39 min

EXAMPLE 248

C₂₉H₄₈N₄O₄S×2C₂HF₃O₂ (776.83)

[M+H]+=549

HPLC (Method 5): retention time=1.39 min

EXAMPLE 249

C₂₈H₄₈N₄O₄S×2HCl (609.69)

[M+H]+=537

HPLC (Method 5): retention time=1.38 min

EXAMPLE 250

C₂₈H₄₈N₄O₄S×2HCl (609.69)

[M+H]+=537

HPLC (Method 11): retention time=1.60 min

EXAMPLE 251

C₂₈H₄₈N₄O₄S×2HCl (609.69)

[M+H]+=537

HPLC (Method 7): retention time=1.71 min

EXAMPLE 252

C₃₀H₄₃N₅O₄S×HCl (606.22)

[M+H]+=570

DC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.29

EXAMPLE 253

C₂₈H₃₉ClN₄O₄S×HCl (599.61)

[M+H]+=563/565

HPLC (Method 5): retention time=1.59 min

EXAMPLE 254

C₂₈H₄₁ClN₄O₄S×HCl (601.63)

[M+H]+=565/567

DC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.46

EXAMPLE 255

C₃₀H₄₅ClN₄O₄S×HCl (629.68)

[M+H]+=593/595

DC: silica gel, dichloromethane/methanol 9:1, Rf value=0.42

EXAMPLE 256

C₂₉H₄₃ClN₄O₄S×HCl (615.66)

[M+H]+=579/581

DC: silica gel, dichloromethane/methanol 9:1, Rf value=0.23

EXAMPLE 257

C₃₀H₃₇N₅O₄S×HCl (600.17)

[M+H]+=564

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.1, Rf value=0.67

EXAMPLE 258

C₃₀H₄₃N₅O₄S (569.76)

[M+H]+=570

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.65

EXAMPLE 259

C₃₀H₄₃ClN₄O₄S×HCl (627.67)

[M+H]+=591/593

DC: silica gel, dichloromethane/methanol 9:1, Rf value=0.20

EXAMPLE 260

C₂₉H₄₃ClN₄O₄S×HCl (615.66)

[M+H]+=579/581

DC: silica gel, dichloromethane/methanol 9:1, Rf value=0.17

EXAMPLE 261

C₂₈H₄₆N₄O₄S×2HCl (607.68)

[M+H]+=535

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.23

EXAMPLE 262

C₃₁H₅₂N₄O₄S×2HCl (649.76)

[M+H]+=577

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.69

EXAMPLE 263

C₂₈H₄₆N₄O₄S (534.76)

[M+H]+=535

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.58

EXAMPLE 264

C₃₁H₅₂N₄O₄S (576.84)

[M+H]+=577

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.56

EXAMPLE 265

C₂₈H₄₆N₄O₄S×2HCl (607.68)

[M+H]+=535

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.58

EXAMPLE 266

C₂₇H₄₆N₄O₄S (522.74)

[M+H]+=523

HPLC (Method 9): retention time=1.30 min

EXAMPLE 267

C₂₇H₄₆N₄O₄S (522.74)

[M+H]+=523

HPLC (Method 9): retention time=1.28 min

EXAMPLE 268

C₂₉H₄₈N₄O₄S×CH₂O₂ (594.81)

[M+H]+=549

HPLC (Method 6): retention time=1.96 min

EXAMPLE 269

C₃₀₉H₄₄N₄O₄S (556.76)

[M+H]+=557

HPLC (Method 9): retention time=1.71 min

EXAMPLE 270

C₂₄H₄₂N₄O₄S×C₂HF₃O₂ (596.70)

[M+H]+=483

HPLC (Method 9): retention time=1.23 min

EXAMPLE 271

C₂₇H₄₆N₄O₄S (522.74)

[M+H]+=523

HPLC (Method 9): retention time=1.23 min

EXAMPLE 272

C₂₅H₄₄N₄O₄S (496.71)

[M+H]+=497

HPLC (Method 9): retention time=1.25 min

EXAMPLE 273

C₂₈H₄₉N₅O₄S×2HCl (624.71)

[M+H]+=552

HPLC (Method 10): retention time=1.06 min

EXAMPLE 274

C₂₉H₅₀N₄O₄S×CH₂O₂ (596.82)

[M+H]+=551

HPLC (Method 9): retention time=1.31 min

EXAMPLE 275

C₂₇H₄₅N₅O₅S×CH₂O₂ (597.77)

[M+H]+=552

HPLC (Method 9): retention time=1.20 min

EXAMPLE 276

C₂₈H₄₈N₄O₄S (536.77)

[M+H]+=537

HPLC (Method 6): retention time=1.32 min

EXAMPLE 277

C₂₇H₄₅N₅O₅S×C₂HF₃O₂ (665.77)

[M+H]+=552

HPLC (Method 9): retention time=1.18 min

EXAMPLE 278

C₂₇H₄₆N₄O₄S×2 C₂HF₃O₂ (750.79)

[M+H]+=523

HPLC (Method 9): retention time=1.29 min

EXAMPLE 279

C₂₄H₃₄ClN₅O₄S (524.08)

[M+H]+=524/526

HPLC (Method 9): retention time=1.60 min

EXAMPLE 280

C₂₃H₃₈N₄O₄S×2C₂HF₃O₂ (694.69)

[M+H]+=467

HPLC (Method 9): retention time=1.16 min

EXAMPLE 281

C₂₆H₃₈ClN₅O₄S×C₂HF₃O₂ (666.15)

[M+H]+=552/554

HPLC (Method 9): retention time=1.68 min

EXAMPLE 282

C₂₆H₄₄N₄O₄S×2HCl (581.64)

[M+H]+=509

HPLC (Method 5): retention time=1.36 min

EXAMPLE 283

C₂₉H₄₈N₄O₄S×2HCl (621.70)

[M+H]+=549

HPLC (Method 5): retention time=1.38 min

EXAMPLE 284

C₂₉H₄₈N₄O₄S (548.78)

[M+H]+=549

HPLC (Method 5): retention time=1.38 min

EXAMPLE 285

C₂₉H₄₈N₄O₄S (548.78)

[M+H]+=549

HPLC (Method 5): retention time=1.36 min

EXAMPLE 286

C₂₉H₄₆F₂N₄O₄S (584.76)

[M+H]+=585

HPLC (Method 5): retention time=1.38 min

EXAMPLE 287

C₂₉H₄₇FN₄O₄S (566.77)

[M+H]+=567

HPLC (Method 5): retention time=1.38 min

EXAMPLE 288

C₂₉H₄₇FN₄O₄S (566.77)

[M+H]+=567

HPLC (Method 5): retention time=1.36 min

EXAMPLE 289

C₂₉H₄₈N₄O₅S (564.78)

[M+H]+=565

HPLC (Method 5): retention time=1.37 min

EXAMPLE 290

C₃₀H₅₀N₄O₄S (562.81)

[M+H]+=563

HPLC (Method 5): retention time=1.39 min

EXAMPLE 291

C₂₉H₅₀N₄O₄S (550.80)

[M+H]+=551

HPLC (Method 5): retention time=1.36 min

EXAMPLE 292

C₃₀H₅₀N₄O₄S (562.81)

[M+H]+=563

HPLC (Method 5): retention time=1.28 min

EXAMPLE 293

C₂₇H₄₇N₅O₄S×3C₂HF₃O₂ (879.83)

[M+H]+=538

HPLC (Method 5): retention time=1.33 min

EXAMPLE 294

C₃₀H₅₀N₄O₄S×2HCl (635.73)

[M+H]+=563

HPLC (Method 5): retention time=1.37 min

EXAMPLE 295

C₂₉H₄₆F₂N₄O₄S×2C₂HF₃O₂ (584.76)

[M+H]+=585

HPLC (Method 5): retention time=1.38 min

EXAMPLE 296

C₂₉H₄₇FN₄O₄S×2C₂HF₃O₂ (794.82)

[M+H]+=567

HPLC (Method 5): retention time=1.35 min

EXAMPLE 297

C₂₉H₄₇FN₄O₄S×2C₂HF₃O₂ (794.82)

[M+H]+=567

HPLC (Method 5): retention time=1.36 min

EXAMPLE 298

C₂₉H₄₈N₄O₅S (564.78)

[M+H]+=565

HPLC (Method 5): retention time=1.36 min

EXAMPLE 299

C₃₀H₅₀N₄O₄S (562.81)

[M+H]+=563

HPLC (Method 5): retention time=1.37 min

EXAMPLE 300

C₂₉H₅₀N₄O₄S (550.80)

[M+H]+=551

HPLC (Method 5): retention time=1.37 min

EXAMPLE 301

C₃₀H₅₀N₄O₄S (562.81)

[M+H]+=563

HPLC (Method 5): retention time=1.37 min

EXAMPLE 302

C₃₀H₅₀N₄O₄S×3C₂HF₃O₂ (877.81)

[M+H]+=536

HPLC (Method 5): retention time=1.34 min

EXAMPLE 303

C₃₀H₅₀N₄O₄S (562.81)

[M+H]+=563

HPLC (Method 5): retention time=1.37 min

EXAMPLE 304

C₂₉H₄₉N₅O₄S×3C₂HF₃O₂ (905.87)

[M+H]+=564

HPLC (Method 5): retention time=1.08 min

EXAMPLE 305

C₂₈H₄₆N₄O₄S×2HCl (607.68)

[M+H]+=535

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.19

EXAMPLE 306

C₂₇H₄₀N₄O₄S×C₂HF₃O₄ (630.72)

[M+H]+=517

HPLC (Method 9): retention time=1.40 min

EXAMPLE 307

C₂₉H₄₈N₄O₄S (548.78)

[M+H]+=549

HPLC (Method 6): retention time=1.24 min

EXAMPLE 308

C₂₇H₄₆N₄O₄S (522.74)

[M+H]+=523

HPLC (Method 9): retention time=1.29 min

EXAMPLE 309

C₂₆H₄₄N₄O₄S (508.72)

[M+H]+=509

HPLC (Method 9): retention time=1.30 min

EXAMPLE 310

C₂₆H₄₄N₄O₄S (508.72)

[M+H]+=509

HPLC (Method 9): retention time=1.23 min

EXAMPLE 311

C₂₆H₄₄N₄O₄S (508.72)

[M+H]+=509

HPLC (Method 6): retention time=1.20 min

EXAMPLE 312

C₂₅H₃₅N₃O₅S×HCl (526.09)

[M+H]+=490

HPLC (Method 10): retention time=1.16 min

EXAMPLE 313

C₂₆H₃₇N₃O₅S×HCl (540.12)

[M+H]+=504

HPLC (Method 10): retention time=1.22 min

EXAMPLE 314

C₂₄H₃₈N₄O₅S×C₂HF₃O₂ (608.67)

[M+H]+=495

HPLC (Method 9): retention time=1.47 min

EXAMPLE 315

C₂₄H₄₀N₄O₄S (480.66)

[M+H]+=481

HPLC (Method 9): retention time=1.21 min

EXAMPLE 316

C₂₄H₄₀N₄O₄S×C₂HF₃O₂ (594.69)

[M+H]+=481

HPLC (Method 9): retention time=1.19 min

EXAMPLE 317

C₂₇H₃₉N₃O₅S×HCl (554.14)

[M+H]+=518

HPLC (Method 5): retention time=1.36 min

EXAMPLE 593

C₂₆H₃₈N₄O₄S×HCl (539.13)

[M+H]+=503

HPLC (Method 5): retention time=1.29 min

EXAMPLE 594

C₂₇H₄₀N₄O₄S×HCl (553.16)

[M+H]+=517

HPLC (Method 5): retention time=1.35 min

EXAMPLE 595

C₂₅H₃₆N₄O₄S×HCl (525.10)

[M+H]+=489

HPLC (Method 5): retention time=1.31 min

EXAMPLE 596

C₂₆H₃₈N₄O₄S×HCl (539.13)

[M+H]+=503

HPLC (Method 5): retention time=1.35 min

EXAMPLE 597

C₂₆H₃₇N₃O₅S×HCl (540.12)

[M+H]+=504

HPLC (Method 10): retention time=1.18 min

EXAMPLE 598

C₂₉H₄₈N₄O₄S×C₂HF₃O₂ (662.81)

[M+H]+=549

HPLC (Method 9): retention time=1.27 min

EXAMPLE 599

C₂₇H₄₅N₅O₄S×3HCl (645.13)

[M+H]+=536

HPLC (Method 5): retention time=1.14 min

EXAMPLE 600

C₂₉H₄₈N₄O₄S×2HCl (621.70)

[M+H]+=549

HPLC (Method 5): retention time=1.16 min

EXAMPLE 601

C₂₉H₄₈N₄O₄S (548.78)

[M+H]+=549

HPLC (Method 5): retention time=1.16 min

EXAMPLE 602

C₃₀H₅₀N₄O₄S×C₂HF₃O₂ (676.83)

[M+H]+=563

HPLC (Method 9): retention time=1.14 min

EXAMPLE 608

C₂₉H₄₈N₄O₄S×C₂HF₃O₂ (662.81)

[M+H]+=549

HPLC (Method 9): retention time=1.30 min

EXAMPLE 609

C₃₀H₅₀N₄O₄S×2HCl (635.73)

[M+H]+=563

HPLC (Method 11): retention time=1.70 min

EXAMPLE 610

C₂₈H₄₈N₄O₄S×2HCl (609.69)

[M+H]+=537

HPLC (Method 11): retention time=1.67 min

EXAMPLE 611

C₂₇H₄₄N₄O₄S×2HCl (593.65)

[M+H]+=521

HPLC (Method 11): retention time=1.61 min

EXAMPLE 636

C₂₉H₄₈N₄O₄S×2HCl (621.70)

[M+H]+=549

HPLC (Method 4): retention time=2.39 min

EXAMPLE 637

C₂₉H₄₈N₄O₄S×2HCl (621.70)

[M+H]+=549

HPLC (Method 4): retention time=2.34 min

The following compounds were prepared analogously to Example 53:

EXAMPLE 318

C₂₃H₃₀N₂O₇S (478.56)

[M+H]+=479

HPLC (Method 6): retention time=3.21 min

EXAMPLE 319

C₂₆H₃₃N₅O₆S (543.64)

[M+H]+=544

HPLC (Method 6): retention time=2.51 min

EXAMPLE 320

C₂₆H₃₈N₄O₆S (534.67)

[M+H]+=535

HPLC (Method 6): retention time=2.48 min

EXAMPLE 321

C₂₆H₃₉₈N₃O₆S (521.67)

[M+H]+=522

HPLC (Method 6): retention time=2.60 min

EXAMPLE 322

C₂₇H₄₁N₃O₅S (519.70)

[M+H]+=520

HPLC (Method 6): retention time=2.61 min

EXAMPLE 323

C₂₇H₄₂N₄O₅S×HCl (571.17)

[M+H]+=535

HPLC (Method 5): retention time=1.57 min

EXAMPLE 324

C₂₉H₃₄N₄O₅S×C₂HF₃O₂ (664.69)

[M+H]+=551

HPLC (Method 5): retention time=1.60 min

EXAMPLE 325

C₂₆H₄₀N₄O₅S×HCl (557.15)

[M+H]+=521

HPLC (Method 5): retention time=1.53 min

EXAMPLE 326

C₂₈H₄₁N₃O₅S×C₂HF₃O₂ (645.73)

[M+H]+=532

HPLC (Method 5): retention time=1.54 min

EXAMPLE 327

C₂₅H₃₇N₃O₅S×HCl (528.11)

[M+H]+=492

HPLC (Method 5): retention time=1.53 min

EXAMPLE 328

C₂₆H₃₉N₃O₆S×C₂HF₃O₂ (635.69)

[M+H]+=522

HPLC (Method 5): retention time=1.53 min

EXAMPLE 329

C₂₆H₃₇N₃O₅S×HCl (540.12)

[M+H]+=504

HPLC (Method 7): retention time=1.93 min

EXAMPLE 330

C₂₆H₃₉N₃O₅S×HCl (542.13)

[M+H]+=506

HPLC (Method 5): retention time=1.54 min

EXAMPLE 331

C₂₈H₄₁N₃O₅S×HCl (568.17)

[M+H]+=532

DC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.30

EXAMPLE 332

C₂₆H₃₇N₃O₅S×HCl (540.12)

[M+H]+=504

HPLC (Method 5): retention time=1.51 min

EXAMPLE 333

C₂₈H₄₂N₄O₅S×HCl (583.18)

[M+H]+=547

HPLC (Method 5): retention time=1.54 min

EXAMPLE 334

C₂₈H₄₂N₄O₅S×HCl (583.18)

[M+H]+=547

HPLC (Method 10): retention time=1.24 min

EXAMPLE 335

C₂₉H₄₄N₄O₅S×HCl (597.21)

[M+H]+=561

HPLC (Method 5): retention time=1.55 min

EXAMPLE 336

C₂₇H₄₅N₃O₅S×HCl (560.19)

[M+H]+=524

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.01, Rf value=0.39

EXAMPLE 337

C₂₇H₃₉N₃O₅S×HCl (554.14)

[M+H]+=518

HPLC (Method 4): retention time=3.4 min

EXAMPLE 338

C₂₈H₄₁N₃O₅S×HCl (568.17)

[M+H]+=532

DC: silica gel, dichloromethane/methanol 9:1, Rf value=0.14

EXAMPLE 339

C₂₄H₃₀N₄O₅S×C₂HF₃O₂ (600.61)

[M+H]+=487

HPLC (Method 6): retention time=2.58 min

EXAMPLE 340

C₂₅H₃₅N₃O₅S×C₂HF₃O₂ (603.65)

[M+H]+=490

HPLC (Method 6): retention time=2.61 min

EXAMPLE 341

C₂₃H₂₉N₅O₅S×C₂HF₃O₂ (601.60)

[M+H]+=488

HPLC (Method 6): retention time=3.28 min

EXAMPLE 342

C₂₇H₃₉FN₄O₆S (566.69)

[M+H]+=567

HPLC (Method 6): retention time=2.59 min

EXAMPLE 343

C₂₅H₃₇FN₄O₅S (524.65)

[M+H]+=525

HPLC (Method 6): retention time=2.59 min

EXAMPLE 344

C₂₇H₃₈N₄O₅S (530.68)

[M+H]+=531

HPLC (Method 6): retention time=2.65 min

EXAMPLE 345

C₂₆H₃₃N₅O₆S (543.64)

[M+H]+=544

HPLC (Method 6): retention time=2.39 min

EXAMPLE 346

C₂₆H₃₅N₅O₅S (529.65)

[M+H]+=530

HPLC (Method 6): retention time=2.43 min

EXAMPLE 347

C₂₈H₄₀N₄O₅S (544.71)

[M+H]+=545

HPLC (Method 6): retention time=2.65 min

EXAMPLE 348

C₂₇H₃₉N₅O₅S (545.70)

[M+H]+=546

HPLC (Method 6): retention time=2.19 min

EXAMPLE 349

C₂₆H₃₉ClN₄O₅S (555.13)

[M+H]+=555/557

HPLC (Method 6): retention time=2.63 min

EXAMPLE 350

C₂₅H₄₄N₄O₅S (512.71)

[M+H]+=513

HPLC (Method 6): retention time=1.94 min

EXAMPLE 351

C₂₇H₄₁N₃O₆S (535.70)

[M+H]+=536

HPLC (Method 6): retention time=2.56 min

EXAMPLE 352

C₂₆H₃₈ClN₃O₆S×CH₂O₂ (602.14)

[M+H]+=556/558

HPLC (Method 6): retention time=2.65 min

EXAMPLE 353

C₃₀H₄₄N₄O₅S (572.76)

[M+H]+=573

HPLC (Method 6): retention time=2.69 min

EXAMPLE 354

C₂₇H₄₂N₄O₅S (534.71)

[M+H]+=535

HPLC (Method 6): retention time=2.54 min

EXAMPLE 355

C₂₄H₄₂N₄O₅S (498.68)

[M+H]+=499

HPLC (Method 6): retention time=1.95 min

EXAMPLE 356

C₂₈H₄₁ClN₄O₅S (581.17)

[M+H]+=581/583

HPLC (Method 6): retention time=2.77 min

EXAMPLE 357

C₂₇H₃₆N₄O₆S (544.66)

[M+H]+=545

HPLC (Method 6): retention time=2.59 min

EXAMPLE 358

C₂₈H₄₁N₃O₆S (547.71)

[M+H]+=548

HPLC (Method 6): retention time=2.59 min

EXAMPLE 359

C₂₅H₄₄N₄O₅S (512.71)

[M+H]+=513

HPLC (Method 6): retention time=1.94 min

EXAMPLE 360

C₂₅H₃₂N₄O₅S (500.61)

[M+H]+=501

HPLC (Method 6): retention time=2.41 min

EXAMPLE 361

C₂₃H₃₁N₅O₅S (489.59)

[M+H]+=490

HPLC (Method 6): retention time=2.46 min

EXAMPLE 362

C₂₇H₃₉N₃O₅S×C₂HF₃O₂ (631.71)

[M+H]+=518

HPLC (Method 6): retention time=2.54 min

EXAMPLE 363

C₂₆H₄₁N₅O₅S×CH₂O₂ (581.73)

[M+H]+=536

HPLC (Method 6): retention time=2.58 min

EXAMPLE 364

C₂₅H₃₉N₅O₅S×CH₂O₂ (567.70)

[M+H]+=522

HPLC (Method 6): retention time=2.31 min

EXAMPLE 365

C₂₇H₃₆N₄O₅S×C₂HF₃O₂ (642.69)

[M+H]+=529

HPLC (Method 6): retention time=2.56 min

EXAMPLE 366

C₂₁H₃₀N₄O₅S (450.55)

[M+H]+=451

HPLC (Method 6): retention time=2.31 min

EXAMPLE 367

C₂₆H₃₄N₄O₅S (514.64)

[M+H]+=515

HPLC (Method 6): retention time=2.51 min

EXAMPLE 368

C₂₉H₄₁N₅O₅S×C₂HF₃O₂ (685.76)

[M+H]+=572

HPLC (Method 6): retention time=2.14 min

EXAMPLE 369

C₂₄H₃₃N₅O₅S×C₂HF₃O₂ (617.64)

[M+H]+=504

HPLC (Method 9): retention time=1.61 min

EXAMPLE 370

C₂₄H₃₃N₅O₅S×C₂HF₃O₂ (617.64)

[M+H]+=504

HPLC (Method 9): retention time=1.59 min

EXAMPLE 371

C₂₇H₄₅N₃O₅S×C₂HF₃O₂ (637.75)

[M+H]+=524

HPLC (Method 9): retention time=1.70 min

EXAMPLE 372

C₂₆H₄₆N₄O₅S (526.73)

[M+H]+=527

HPLC (Method 5): retention time=1.43 min

EXAMPLE 373

C₂₈H₄₁N₃O₅S×C₂HF₃O₂ (645.73)

[M+H]+=532

HPLC (Method 5): retention time=1.56 min

EXAMPLE 374

C₂₈H₄₃N₅O₅S×C₂HF₃O₂ (675.76)

[M+H]+=562

HPLC (Method 5): retention time=1.41 min

EXAMPLE 375

C₂₆H₃₉N₅O₅S×C₂HF₃O₂ (647.71)

[M+H]+=534

HPLC (Method 5): retention time=1.42 min

EXAMPLE 376

C₂₈H₄₁N₃O₆S (547.71)

[M+H]+=548

HPLC (Method 5): retention time=1.53 min

EXAMPLE 377

C₂₆H₄₁N₅O₅S (535.70)

[M+H]+=536

HPLC (Method 5): retention time=1.42 min

EXAMPLE 378

C₂₉H₄₄N₄O₅S×HCl (597.21)

[M+H]+=561

HPLC (Method 7): retention time=1.91 min

EXAMPLE 379

C₂₉H₄₃N₃O₅S×C₂HF₃O₂ (659.76)

[M+H]+=546

HPLC (Method 5): retention time=1.59 min

EXAMPLE 380

C₂₈H₄₃N₅O₅S×2C₂HF₃O₂ (789.78)

[M+H]+=562

HPLC (Method 5): retention time=1.40 min

EXAMPLE 381

C₃₀H₄₆N₄O₅S×C₂HF₃O₂ (688.80)

[M+H]+=575

HPLC (Method 5): retention time=1.56 min

EXAMPLE 382

C₂₅H₃₉N₅O₅S×2HCl (594.60)

[M+H]+=522

HPLC (Method 5): retention time=1.40 min

EXAMPLE 383

C₂₆H₄₆N₄O₅S×2HCl (599.65)

[M+H]+=527

HPLC (Method 5): retention time=1.41 min

EXAMPLE 384

C₂₇H₄₆N₄O₅S×HCl (575.20)

[M+H]+=539

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.01, Rf value=0.35

EXAMPLE 385

C₂₈H₄₂N₄O₅S×HCl (583.18)

[M+H]+=547

DC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.32

EXAMPLE 386

C₂₈H₄₁N₃O₅S×HCl (568.17)

[M+H]+=532

DC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.35

EXAMPLE 387

C₂₆H₄₄N₄O₅S×HCl (561.18)

[M+H]+=525

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.01, Rf value=0.12

EXAMPLE 388

C₂₉H₄₄N₄O₅S×HCl (597.21)

[M+H]+=561

DC: silica gel, dichloromethane/methanol 9:1, Rf value=0.30

EXAMPLE 389

C₂₈H₄₄N₄O₅S×HCl (585.20)

[M+H]+=549

DC: silica gel, dichloromethane/methanol 9:1, Rf value=0.15

EXAMPLE 390

C₂₈H₄₇N₃O₅S×HCl (574.22)

[M+H]+=538

DC: silica gel, dichloromethane/methanol 9:1, Rf value=0.05

EXAMPLE 391

C₂₆H₄₅N₃O₅S×HCl (548.18)

[M+H]+=512

HPLC (Method 5): retention time=1.56 min

EXAMPLE 392

C₂₆H₄₃N₃O₅S×HCl (546.16)

[M+H]+=510

DC: silica gel, dichloromethane/methanol 9:1, Rf value=0.05

EXAMPLE 393

C₂₅H₄₂N₄O₅S×2HCl (583.61)

[M+H]+=511

DC: silica gel, dichloromethane/ethanol/ammonia 9:1:0.1, Rf value=0.22

EXAMPLE 394

C₂₅H₄₂N₄O₅S×2HCl (583.61)

[M+H]+=511

HPLC (Method 5): retention time=1.37 min

EXAMPLE 395

C₂₅H₄₃N₃O₅S×HCl (534.15)

[M+H]+=498

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.01, Rf value=0.58

EXAMPLE 396

C₂₅H₄₃N₃O₅S×HCl (534.15)

[M+H]+=498

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.01, Rf value=0.57

EXAMPLE 397

C₂₆H₄₄N₄O₅S×2HCl (597.64)

[M+H]+=525

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.52

EXAMPLE 398

C₂₇H₄₆N₄O₅S×2HCl (611.67)

[M+H]+=539

HPLC (Method 12): retention time=2.45 min

EXAMPLE 399

C₂₇H₄₆N₄O₅S×2HCl (611.67)

[M+H]+=539

HPLC (Method 12): retention time=2.35 min

EXAMPLE 400

C₂₆H₄₄N₄O₅S×2HCl (597.64)

[M+H]+=525

HPLC (Method 12): retention time=2.3 min

EXAMPLE 401

C₂₆H₄₄N₄O₅S×2HCl (597.64)

[M+H]+=525

HPLC (Method 12): retention time=2.3 min

EXAMPLE 402

C₂₈H₄₁N₃O₆S (547.71)

[M+H]+=548

HPLC (Method 9): retention time=1.7 min

EXAMPLE 403

C₂₇H₃₆N₄O₆S (544.66)

[M+H]+=545

HPLC (Method 9): retention time=1.69 min

EXAMPLE 404

C₂₆H₃₇N₅O₅S (531.67)

[M+H]+=532

HPLC (Method 6): retention time=1.56 min

EXAMPLE 405

C₂₆H₃₉FN₄O₅S (538.68)

[M+H]+=539

HPLC (Method 6): retention time=2.60 min

EXAMPLE 406

C₂₆H₄₆N₄O₅S×2HCl (599.65)

[M+H]+=527

HPLC (Method 7): retention time=1.78 min

EXAMPLE 407

C₂₆H₄₆N₄O₅S×2HCl (599.65)

[M+H]+=527

HPLC (Method 7): retention time=1.77 min

EXAMPLE 408

C₂₆H₃₆N₄O₅S (516.65)

[M+H]+=517

HPLC (Method 9): retention time=1.65 min

EXAMPLE 409

C₂₅H₄₂N₄O₆S×C₂HF₃O₂ (640.71)

[M+H]+=527

HPLC (Method 9): retention time=1.55 min

EXAMPLE 410

C₂₇H₄₄N₄O₆S×C₂HF₃O₂ (666.75)

[M+H]+=553

HPLC (Method 9): retention time=1.57 min

EXAMPLE 411

C₂₆H₄₄N₄O₆S×C₂HF₃O₂ (654.74)

[M+H]+=541

HPLC (Method 9): retention time=1.57 min

EXAMPLE 412

C₂₇H₄₅N₃O₅S×C₂HF₃O₂ (637.75)

[M+H]+=524

HPLC (Method 6): retention time=1.71 min

EXAMPLE 413

C₂₃H₃₀N₄O₅S (474.57)

[M+H]+=475

HPLC (Method 9): retention time=1.53 min

EXAMPLE 414

C₂₁H₃₅N₃O₅S (441.59)

[M+H]+=442

HPLC (Method 9): retention time=1.48 min

EXAMPLE 415

C₂₈H₄₆N₄O₆S×C₂HF₃O₂ (680.78)

[M+H]+=567

HPLC (Method 9): retention time=1.60 min

EXAMPLE 416

C₂₇H₄₄N₄O₆S×C₂HF₃O₂ (666.75)

[M+H]+=553

HPLC (Method 9): retention time=1.57 min

EXAMPLE 417

C₂₄H₄₀N₄O₆S×C₂HF₃O₂ (626.69)

[M+H]+=513

HPLC (Method 9): retention time=1.53 min

EXAMPLE 418

C₃₀H₄₃N₃O₆S×CH₂O₂ (619.77)

[M+H]+=574

HPLC (Method 9): retention time=1.73 min

EXAMPLE 419

C₃₁H₅₂N₄O₅S×C₂HF₃O₂ (706.86)

[M+H]+=593

HPLC (Method 9): retention time=1.34 min

EXAMPLE 420

C₂₇H₄₆N₄O₅S (538.74)

[M+H]+=539

HPLC (Method 9): retention time=1.43 min

EXAMPLE 421

C₂₆H₄₄N₄O₅S×C₂HF₃O₂ (638.74)

[M+H]+=525

HPLC (Method 6): retention time=1.53 min

EXAMPLE 422

C₂₆H₄₄N₄O₅S×C₂HF₃O₂ (638.74)

[M+H]+=525

HPLC (Method 6): retention time=1.41 min

EXAMPLE 423

C₂₉H₄₉N₃O₅S×C₂HF₃O₂ (665.81)

[M+H]+=552

HPLC (Method 9): retention time=1.74 min

EXAMPLE 424

C₂₉H₄₁N₃O₅S (543.72)

[M+H]+=544

HPLC (Method 6): retention time=1.73 min

EXAMPLE 425

C₂₆H₄₃N₃O₅S×C₂HF₃O₂ (623.73)

[M+H]+=510

HPLC (Method 9): retention time=1.63 min

EXAMPLE 426

C₂₂H₃₇N₃O₅S (455.61)

[M+H]+=456

HPLC (Method 6): retention time=1.55 min

EXAMPLE 427

C₂₆H₄₄N₄O₆S (540.72)

[M+H]+=541

HPLC (Method 6): retention time=1.59 min

EXAMPLE 428

C₂₇H₄₈N₄O₅S×2HCl (613.68)

[M+H]+=541

HPLC (Method 7): retention time=1.65 min

EXAMPLE 429

C₂₇H₄₈N₄O₅S×2HCl (613.68)

[M+H]+=541

HPLC (Method 11): retention time=1.64 min

EXAMPLE 430

C₂₆H₄₆N₄O₅S×2C₂HF₃O₂ (754.78)

[M+H]+=527

HPLC (Method 5): retention time=1.16 min

EXAMPLE 431

C₂₆H₄₆N₄O₅S×2HCl (599.65)

[M+H]+=527

HPLC (Method 7): retention time=1.82 min

EXAMPLE 432

C₂₆H₄₆N₄O₅S×2HCl (599.65)

[M+H]+=527

HPLC (Method 7): retention time=1.82 min

EXAMPLE 433

C₂₆H₄₄N₄O₅S×2HCl (597.64)

[M+H]+=525

HPLC (Method 12): retention time=2.3 min

EXAMPLE 434

C₂₇H₄₆N₄O₅S×2HCl (611.67)

[M+H]+=539

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.65

EXAMPLE 435

C₂₇H₄₅N₃O₅S (523.73)

[M+H]+=524

HPLC (Method 6): retention time=1.29 min

EXAMPLE 436

C₂₄H₄₀N₄O₅S×CH₂O₂ (542.69)

[M+H]+=497

HPLC (Method 9): retention time=1.25 min

EXAMPLE 437

C₂₆H₄₄N₄O₅S×CH₂O₂ (570.74)

[M+H]+=525

HPLC (Method 9): retention time=1.31 min

EXAMPLE 438

C₂₅H₄₂N₄O₅S×CH₂O₂ (556.72)

[M+H]+=511

HPLC (Method 9): retention time=1.31 min

EXAMPLE 439

C₂₇H₄₅N₃O₅S (523.73)

[M+H]+=524

HPLC (Method 6): retention time=1.67 min

EXAMPLE 440

C₂₅H₄₄N₄O₅S×C₂HF₃O₂ (626.73)

[M+H]+=513

HPLC (Method 9): retention time=1.29 min

EXAMPLE 441

C₂₈H₄₈N₄O₅S×2HCl (625.69)

[M+H]+=553

HPLC (Method 9): retention time=1.35 min

EXAMPLE 442

C₂₈H₄₈N₄O₅S×2HCl (625.69)

[M+H]+=553

HPLC (Method 9): retention time=1.32 min

EXAMPLE 443

C₂₈H₄₈N₄O₅S (552.77)

[M+H]+=553

HPLC (Method 9): retention time=1.37 min

EXAMPLE 444

C₂₈H₄₈N₄O₅S×CH₂O₂ (598.80)

[M+H]+=553

HPLC (Method 9): retention time=1.35 min

EXAMPLE 445

C₃₀H₄₃ClN₄O₅S (607.21)

[M+H]+=608

HPLC (Method 6): retention time=1.80 min

EXAMPLE 446

C₂₆H₄₄N₄O₅S×2HCl (597.64)

[M+H]+=525

HPLC (Method 12): retention time=2.4 min

EXAMPLE 447

C₂₆H₄₄N₄O₅S×2HCl (597.64)

[M+H]+=525

HPLC (Method 12): retention time=2.4 min

EXAMPLE 448

C₂₉H₄₈N₄O₅S×2HCl (637.70)

[M+H]+=565

HPLC (Method 12): retention time=2.3 min

EXAMPLE 449

C₂₉H₄₈N₄O₅S×2HCl (637.70)

[M+H]+=565

HPLC (Method 12): retention time=2.92 min

EXAMPLE 450

C₂₆H₄₄N₄O₅S×2HCl (597.64)

[M+H]+=525

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.60

EXAMPLE 451

C₂₇H₄₆N₄O₅S×2HCl (611.67)

[M+H]+=539

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.62

EXAMPLE 452

C₂₇H₄₅N₃O₅S×HCl (560.19)

[M+H]+=524

HPLC (Method 12): retention time=3.01 min

EXAMPLE 453

C₂₈H₄₈N₄O₅S×2HCl (625.69)

[M+H]+=553

HPLC (Method 12): retention time=2.45 min

EXAMPLE 454

C₂₅H₄₂N₄O₅S×2HCl (583.61)

[M+H]+=511

HPLC (Method 12): retention time=2.33 min

EXAMPLE 455

C₂₄H₄₂N₄O₅S×C₂HF₃O₂ (612.70)

[M+H]+=499

HPLC (Method 9): retention time=1.32 min

EXAMPLE 456

C₂₅H₄₂N₄O₅S×2C₂HF₃O₂ (738.74)

[M+H]+=511

HPLC (Method 9): retention time=1.24 min

EXAMPLE 457

C₂₅H₄₂N₄O₅S×2C₂HF₃O₂ (738.74)

[M+H]+=511

HPLC (Method 9): retention time=1.27 min

EXAMPLE 458

C₂₈H₄₆N₄O₅S×CH₂O₂ (596.78)

[M+H]+=551

HPLC (Method 6): retention time=1.31 min

EXAMPLE 459

C₂₆H₄₃N₃O₅S×C₂HF₃O₂ (623.73)

[M+H]+=510

HPLC (Method 9): retention time=1.62 min

EXAMPLE 460

C₂₅H₄₀N₄O₆S×C₂HF₃O₂ (638.70)

[M+H]+=525

HPLC (Method 9): retention time=1.49 min

EXAMPLE 461

C₂₆H₄₂N₄O₆S×C₂HF₃O₂ (652.72)

[M+H]+=539

HPLC (Method 9): retention time=1.51 min

EXAMPLE 462

C₂₆H₄₂N₄O₆S×C₂HF₃O₂ (652.72)

[M+H]+=539

HPLC (Method 9): retention time=1.52 min

EXAMPLE 463

C₂₈H₄₇N₃O₅S (537.76)

[M+H]+=538

HPLC (Method 9): retention time=1.71 min

EXAMPLE 464

C₂₈H₄₈N₄O₅S (552.77)

[M+H]+=553

HPLC (Method 9): retention time=1.39 min

EXAMPLE 465

C₂₈H₄₆N₄O₅S×CH₂O₂ (596.78)

[M+H]+=551

HPLC (Method 6): retention time=1.32 min

EXAMPLE 466

C₂₆H₄₆N₄O₅S (526.73)

[M+H]+=527

HPLC (Method 9): retention time=1.27 min

EXAMPLE 467

C₂₄H₄₁N₃O₅S (483.67)

[M+H]+=484

HPLC (Method 6): retention time=1.60 min

EXAMPLE 468

C₃₀H₅₀N₄O₅S×CH₂O₂ (624.83)

[M+H]+=579

HPLC (Method 6): retention time=1.31 min

EXAMPLE 469

C₂₃H₃₆Cl₂N₄O₅S (551.53)

[M+H]+=551/553/555

HPLC (Method 9): retention time=1.30 min

EXAMPLE 470

C₂₆H₄₃N₃O₅S (509.70)

[M+H]+=510

HPLC (Method 6): retention time=1.67 min

EXAMPLE 471

C₃₀H₅₀N₄O₅S×C₂HF₃O₂ (692.83)

[M+H]+=579

HPLC (Method 9): retention time=1.39 min

EXAMPLE 472

C₃₀H₅₀N₄O₅S×C₂HF₃O₂ (692.83)

[M+H]+=579

HPLC (Method 9): retention time=1.39 min

EXAMPLE 473

C₂₉H₅₀N₄O₅S×C₂HF₃O₂ (680.82)

[M+H]+=567

HPLC (Method 9): retention time=1.40 min

EXAMPLE 474

C₂₉H₄₉N₃O₅S (551.78)

[M+H]+=552

HPLC (Method 9): retention time=1.72 min

EXAMPLE 475

C₂₈H₄₆N₄O₆S×C₂HF₃O₂ (680.78)

[M+H]+=567

HPLC (Method 9): retention time=1.60 min

EXAMPLE 476

C₂₉H₅₀N₄O₅S×C₂HF₃O₂ (680.82)

[M+H]+=567

HPLC (Method 9): retention time=1.41 min

EXAMPLE 477

C₂₇H₄₅N₃O₅S×C₂HF₃O₂ (637.75)

[M+H]+=524

HPLC (Method 9): retention time=1.69 min

EXAMPLE 478

C₂₉H₄₈N₄O₅S×2HCl (637.70)

[M+H]+=565

HPLC (Method 12): retention time=2.4 min

EXAMPLE 479

C₂₇H₄₄N₄O₆S×C₂HF₃O₂ (666.75)

[M+H]+=553

HPLC (Method 9): retention time=1.61 min

EXAMPLE 480

C₂₆H₄₂N₄O₆S×C₂HF₃O₂ (652.72)

[M+H]+=539

HPLC (Method 9): retention time=1.60 min

EXAMPLE 481

C₂₆H₄₂N₄O₆S (538.70)

[M+H]+=539

HPLC (Method 9): retention time=1.47 min

EXAMPLE 482

C₂₅H₄₀N₄O₆S (524.67)

[M+H]+=525

HPLC (Method 9): retention time=1.48 min

EXAMPLE 575

C₂₆H₄₄N₄O₅S (524.72)

[M+H]+=525

HPLC (Method 9): retention time=1.30 min

EXAMPLE 576

C₂₇H₄₆N₄O₅S (538.74)

[M+H]+=539

HPLC (Method 9): retention time=1.34 min

EXAMPLE 577

C₂₈H₄₆N₄O₅S×2HCl (623.68)

[M+H]+=551

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.71

EXAMPLE 578

C₂₇H₄₄N₄O₆S×C₂HF₃O₂ (666.75)

[M+H]+=553

HPLC (Method 9): retention time=1.62 min

EXAMPLE 579

C₂₆H₄₄N₄O₅S×2C₂HF₃O₂ (752.76)

[M+H]+=525

HPLC (Method 9): retention time=1.33 min

EXAMPLE 580

C₂₆H₄₂N₄O₆S×C₂HF₃O₂ (652.72)

[M+H]+=539

HPLC (Method 9): retention time=1.50 min

EXAMPLE 581

C₂₅H₄₄N₄O₅S (512.71)

[M+H]+=513

HPLC (Method 9): retention time=1.27 min

EXAMPLE 582

C₂₈H₄₇N₃O₅S×C₂HF₃O₂ (651.78)

[M+H]+=538

HPLC (Method 9): retention time=1.71 min

EXAMPLE 583

C₂₇H₄₆N₄O₅S (538.74)

[M+H]+=539

HPLC (Method 9): retention time=1.37 min

EXAMPLE 584

C₂₇H₄₆N₄O₅S (538.74)

[M+H]+=539

HPLC (Method 9): retention time=1.44 min

EXAMPLE 585

C₂₅H₄₃N₃O₆S×HCl (550.15)

[M+H]+=514

HPLC (Method 5): retention time=1.34 min

EXAMPLE 586

C₂₉H₅₀N₄O₅S×2HCl (639.72)

[M+H]+=567

HPLC (Method 5): retention time=1.21 min

EXAMPLE 587

C₂₉H₅₀N₄O₅S×2HCl (639.72)

[M+H]+=567

HPLC (Method 5): retention time=1.20 min

EXAMPLE 588

C₃₂H₅₄N₄O₅S×C₂HF₃O₂ (720.88)

[M+H]+=607

HPLC (Method 9): retention time=1.37 min

EXAMPLE 589

C₂₆H₄₄N₄O₅S×2C₂HF₃O₂ (752.76)

[M+H]+=525

HPLC (Method 9): retention time=1.41 min

EXAMPLE 590

C₂₅H₄₄N₄O₅S (512.71)

[M+H]+=513

HPLC (Method 9): retention time=1.35 min

EXAMPLE 591

C₂₈H₄₈N₄O₅S×2C₂HF₃O₂ (780.82)

[M+H]+=553

HPLC (Method 9): retention time=1.40 min

EXAMPLE 592

C₂₆H₄₃N₃O₅S (509.70)

[M+H]+=510

HPLC (Method 9): retention time=1.70 min

EXAMPLE 612

C₂₇H₄₅N₃O₆S×HCl (576.19)

[M+H]+=540

HPLC (Method 5): retention time=1.37 min

EXAMPLE 613

C₂₅H₄₃N₃O₆S×HCl (550.15)

[M+H]+=514

HPLC (Method 5): retention time=1.36 min

EXAMPLE 614

C₂₇H₄₅N₃O₆S×HCl (576.19)

[M+H]+=540

HPLC (Method 5): retention time=1.38 min

EXAMPLE 615

C₂₇H₄₇N₃O₅S×HCl (562.21)

[M+H]+=526

HPLC (Method 4): retention time=3.0 min

EXAMPLE 616

C₂₈H₄₇N₃O₅S×HCl (574.22)

[M+H]+=538

HPLC (Method 4): retention time=3.1 min

EXAMPLE 617

C₂₆H₄₄N₄O₅S (524.72)

[M+H]+=525

HPLC (Method 9): retention time=1.32 min

EXAMPLE 618

C₂₇H₄₆N₄O₅S (538.74)

[M+H]+=539

HPLC (Method 9): retention time=1.57 min

EXAMPLE 619

C₂₇H₄₅N₃O₆S (539.73)

[M+H]+=540

HPLC (Method 9): retention time=1.65 min

EXAMPLE 620

C₂₅H₄₃N₃O₅S (497.69)

[M+H]+=498

HPLC (Method 9): retention time=1.65 min

EXAMPLE 621

C₂₈H₄₇N₃O₅S×HCl (574.22)

[M+H]+=538

HPLC (Method 9): retention time=1.68 min

EXAMPLE 622

C₂₅H₄₁N₃O₅S×C₂HF₃O₂ (609.70)

[M+H]+=496

HPLC (Method 9): retention time=1.62 min

EXAMPLE 623

C₂₇H₄₄N₄O₆S×C₂HF₃O₂ (666.76)

[M+H]+=553

HPLC (Method 9): retention time=1.57 min

EXAMPLE 624

C₂₆H₄₄N₄O₆S×C₂HF₃O₂ (654.75)

[M+H]+=541

HPLC (Method 9): retention time=1.56 min

EXAMPLE 625

C₂₆H₄₃N₅O₆S×C₂HF₃O₂ (667.74)

[M+H]+=554

HPLC (Method 9): retention time=1.00 min

EXAMPLE 626

C₂₇H₄₅N₅O₆S×C₂HF₃O₂ (681.77)

[M+H]+=568

HPLC (Method 9): retention time=1.03 min

EXAMPLE 627

C₂₄H₄₀N₄O₆S×C₂HF₃O₂ (626.69)

[M+H]+=513

HPLC (Method 9): retention time=1.50 min

EXAMPLE 628

C₂₆H₄₂N₄O₆S×C₂HF₃O₂ (654.72)

[M+H]+=539

HPLC (Method 9): retention time=1.55 min

EXAMPLE 629

C₂₅H₄₂N₄O₆S×C₂HF₃O₂ (640.71)

[M+H]+=527

HPLC (Method 9): retention time=1.63 min

EXAMPLE 630

C₂₇H₄₄N₄O₆S (552.73)

[M+H]+=553

HPLC (Method 9): retention time=1.65 min

EXAMPLE 638

C₂₈H₄₇N₃O₆S×HCl (590.22)

[M+H]+=554

HPLC (Method 5): retention time=1.44 min

EXAMPLE 639

C₂₇H₄₄N₄O₆S×C₂HF₃O₂ (666.75)

[M+H]+=553

HPLC (Method 9): retention time=1.59 min

EXAMPLE 640

C₂₇H₄₄N₄O₆S×C₂HF₃O₂ (666.75)

[M+H]+=553

HPLC (Method 9): retention time=1.61 min

EXAMPLE 641

C₂₆H₄₄N₄O₆S×C₂HF₃O₂ (590.22)

[M+H]+=541

HPLC (Method 9): retention time=1.56 min

EXAMPLE 642

C₂₇H₄₄N₄O₆S×C₂HF₃O₂ (666.75)

[M+H]+=553

HPLC (Method 9): retention time=1.55 min

EXAMPLE 643

C₂₆H₄₂N₄O₆S×C₂HF₃O₂ (652.72)

[M+H]+=539

HPLC (Method 9): retention time=1.55 min

EXAMPLE 644

C₂₅H₃₈F₃N₃O₄S (533.66)

[M+H]+=534

EXAMPLE 645

C₂₅H₃₈F₃N₃O₄S (533.66)

[M+H]+=534

EXAMPLE 646

C₂₄H₃₇Cl₂N₃O₄S (534.55)

[M+H]+=535

EXAMPLE 647

C₂₅H₃₇ClF₃N₃O₄S (568.10)

[M+H]+=569

The following compounds wurden analogously to Example 121 prepared:

EXAMPLE 483

C₂₅H₃₄N₄O₅S×C₂HF₃O₂ (616.65)

[M+H]+=503

HPLC (Method 6): retention time=2.30 min

EXAMPLE 484

C₂₅H₃₆N₄O₅S×HCl (541.10)

[M+H]+=505

HPLC (Method 5): retention time=1.49 min

EXAMPLE 485

C₂₈H₃₉FN₄O₅S×C₂HF₃O₂ (676.72)

[M+H]+=563

HPLC (Method 5): retention time=1.55 min

EXAMPLE 486

C₂₆H₃₆N₄O₅S×HCl (553.11)

[M+H]+=517

HPLC (Method 11): retention time=1.73 min

EXAMPLE 487

C₂₅H₃₄N₄O₅S×C₂HF₃O₂ (616.65)

[M+H]+=503

HPLC (Method 5): retention time=1.49 min

EXAMPLE 488

C₂₇H₃₆N₄O₅S×C₂HF₃O₂ (642.69)

[M+H]+=529

HPLC (Method 5): retention time=1.50 min

EXAMPLE 489

C₂₇H₃₈N₄O₅S×C₂HF₃O₂ (644.70)

[M+H]+=531

HPLC (Method 5): retention time=1.54 min

EXAMPLE 490

C₂₆H₃₆N₄O₆S×C₂HF₃O₂ (646.68)

[M+H]+=533

HPLC (Method 5): retention time=1.51 min

EXAMPLE 491

C₂₇H₄₁N₅O₅S×HCl (584.17)

[M+H]+=548

HPLC (Method 5): retention time=1.53 min

EXAMPLE 492

C₂₆H₃₉N₅O₅S×HCl (570.15)

[M+H]+=534

HPLC (Method 5): retention time=1.52 min

EXAMPLE 493

C₂₆H₃₈N₄O₅S×HCl (555.13)

[M+H]+=519

HPLC (Method 5): retention time=1.51 min

EXAMPLE 494

C₂₆H₃₃N₅O₅S (527.64)

[M+H]+=528

HPLC (Method 4): retention time=3.0 min

EXAMPLE 495

C₂₈H₄₀N₄O₅S×HCl (581.17)

[M+H]+=545

HPLC (Method 4): retention time=3.1 min

EXAMPLE 496

C₂₆H₃₆N₄O₅S×HCl (553.11)

[M+H]+=517

HPLC (Method 5): retention time=1.48 min

EXAMPLE 497

C₂₈H₄₁N₅O₅S×HCl (596.18)

[M+H]+=560

HPLC (Method 5): retention time=1.52 min

EXAMPLE 498

C₂₈H₄₁N₅O₅S×HCl (596.18)

[M+H]+=560

HPLC (Method 5): retention time=1.52 min

EXAMPLE 499

C₂₉H₄₃N₅O₅S×HCl (610.21)

[M+H]+=574

HPLC (Method 5): retention time=1.57 min

EXAMPLE 500

C₂₇H₄₄N₄O₅S×HCl (573.19)

[M+H]+=537

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.01, Rf value=0.66

EXAMPLE 501

C₂₇H₃₈N₄O₅S×HCl (567.14)

[M+H]+=531

HPLC (Method 4): retention time=3.0 min

EXAMPLE 502

C₂₈H₄₀N₄O₅S×HCl (581.17)

[M+H]+=545

DC: silica gel, dichloromethane/methanol 9:1, Rf value=0.18

EXAMPLE 503

C₂₈H₄₁N₅O₅S×HCl (596.18)

[M+H]+=560

DC: silica gel, ethyl acetate/methanol/ammonia 9:1:0.1, Rf value=0.42

EXAMPLE 504

C₂₇H₃₈N₆O₅S (558.69)

[M+H]+=559

HPLC (Method 6): retention time=2.23 min

EXAMPLE 505

C₂₈H₃₉N₅O₅S (557.71)

[M+H]+=558

HPLC (Method 6): retention time=2.35 min

EXAMPLE 506

C₂₆H₃₈ClN₅O₅S×CH₂O₂ (614.16)

[M+H]+=568/570

HPLC (Method 6): retention time=2.55 min

EXAMPLE 507

C₂₇H₄₀N₄O₆S (548.70)

[M+H]+=549

HPLC (Method 6): retention time=2.49 min

EXAMPLE 508

C₂₅H₄₃N₅O₅S (525.71)

[M+H]+=526

HPLC (Method 6): retention time=1.85 min

EXAMPLE 509

C₃₀H₄₃N₅O₅S (585.76)

[M+H]+=586

HPLC (Method 6): retention time=2.66 min

EXAMPLE 510

C₂₇H₃₈N₄O₅S (530.68)

[M+H]+=531

HPLC (Method 6): retention time=2.52 min

EXAMPLE 511

C₂₇H₄₁N₅O₅S (547.71)

[M+H]+=548

HPLC (Method 6): retention time=2.44 min

EXAMPLE 512

C₂₆H₃₇ClN₄O₆S (569.11)

[M+H]+=570

HPLC (Method 6): retention time=2.56 min

EXAMPLE 513

C₂₄H₄₁N₅O₅S (511.68)

[M+H]+=512

HPLC (Method 6): retention time=1.80 min

EXAMPLE 514

C₂₈H₄₀ClN₅O₅S (594.17)

[M+H]+=594/596

HPLC (Method 6): retention time=2.68 min

EXAMPLE 515

C₂₇H₃₅N₅O₆S (557.66)

[M+H]+=558

HPLC (Method 6): retention time=2.51 min

EXAMPLE 516

C₂₈H₄₀N₄O₆S (560.71)

[M+H]+=561

HPLC (Method 6): retention time=2.51 min

EXAMPLE 517

C₂₅H₃₁N₅O₅S (513.61)

[M+H]+=514

HPLC (Method 6): retention time=2.35 min

EXAMPLE 518

C₂₇H₃₉N₅O₅S×C₂HF₃O₂ (659.72)

[M+H]+=546

HPLC (Method 6): retention time=2.44 min

EXAMPLE 519

C₂₃H₃₀N₆O₅S (502.59)

[M+H]+=503

HPLC (Method 6): retention time=2.37 min

EXAMPLE 520

C₂₇H₃₉N₅O₅S×C₂HF₃O₂ (659.72)

[M+H]+=546

HPLC (Method 6): retention time=2.52 min

EXAMPLE 521

C₂₈H₄₁N₅O₅S×C₂HF₃O₂ (673.75)

[M+H]+=560

HPLC (Method 6): retention time=2.58 min

EXAMPLE 522

C₂₈H₃₉N₅O₅S×C₂HF₃O₂ (671.73)

[M+H]+=558

HPLC (Method 6): retention time=2.57 min

EXAMPLE 523

C₂₇H₃₈N₄O₅S×C₂HF₃O₂ (644.70)

[M+H]+=531

HPLC (Method 6): retention time=2.45 min

EXAMPLE 524

C₂₆H₄₀N₆O₅S (548.70)

[M+H]+=549

HPLC (Method 6): retention time=2.52 min

EXAMPLE 525

C₂₉H₄₃N₅O₅S×C₂HF₃O₂ (687.77)

[M+H]+=574

HPLC (Method 6): retention time=2.72 min

EXAMPLE 526

C₃₀H₄₃N₅O₅S (585.76)

[M+H]+=586

HPLC (Method 6): retention time=2.70 min

EXAMPLE 527

C₂₅H₃₈N₆O₅S×CH₂O₂ (580.70)

[M+H]+=535

HPLC (Method 6): retention time=2.16 min

EXAMPLE 528

C₂₇H₃₅N₅O₅S×C₂HF₃O₂ (655.69)

[M+H]+=542

HPLC (Method 6): retention time=2.48 min

EXAMPLE 529

C₂₈H₄₁N₅O₅S×C₂HF₃O₂ (673.75)

[M+H]+=560

HPLC (Method 6): retention time=2.61 min

EXAMPLE 530

C₂₁H₂₉N₅O₅S (463.55)

[M+H]+=464

HPLC (Method 9): retention time=1.47 min

EXAMPLE 531

C₂₆H₃₃N₅O₅S (527.64)

[M+H]+=528

HPLC (Method 9): retention time=1.60 min

EXAMPLE 532

C₂₉H₄₀N₆O₅S (584.73)

[M+H]+=585

HPLC (Method 9): retention time=1.37 min

EXAMPLE 533

C₂₄H₃₂N₆O₅S×C₂HF₃O₂ (630.64)

[M+H]+=517

HPLC (Method 9): retention time=1.58 min

EXAMPLE 534

C₂₄H₃₂N₆O₅S×C₂HF₃O₂ (630.64)

[M+H]+=517

HPLC (Method 9): retention time=1.57 min

EXAMPLE 535

C₂₇H₄₄N₄O₅S×C₂HF₃O₂ (650.75)

[M+H]+=537

HPLC (Method 9): retention time=1.68 min

EXAMPLE 536

C₂₆H₄₅N₅O₅S×2HCl (612.65)

[M+H]+=540

HPLC (Method 5): retention time=1.39 min

EXAMPLE 537

C₂₈H₄₀N₄O₅S×C₂HF₃O₂ (658.73)

[M+H]+=545

HPLC (Method 5): retention time=1.53 min

EXAMPLE 538

C₂₆H₃₈N₄O₆S×C₂HF₃O₂ (648.69)

[M+H]+=535

HPLC (Method 5): retention time=1.43 min

EXAMPLE 539

C₂₈H₄₀N₄O₆S (560.71)

[M+H]+=561

HPLC (Method 5): retention time=1.50 min

EXAMPLE 540

C₂₆H₄₀N₆O₅S (548.70)

[M+H]+=549

HPLC (Method 5): retention time=1.39 min

EXAMPLE 541

C₂₉H₄₃N₅O₅S×HCl (610.21)

[M+H]+=574

HPLC (Method 7): retention time=1.88 min

EXAMPLE 542

C₂₉H₄₂N₄O₅S×C₂HF₃O₂ (672.76)

[M+H]+=559

HPLC (Method 5): retention time=1.55 min

EXAMPLE 543

C₂₅H₃₈N₆O₅S×2HCl (607.59)

[M+H]+=535

HPLC (Method 5): retention time=1.39 min

EXAMPLE 544

C₃₀H₄₅N₅O₅S×C₂HF₃O₂ (701.80)

[M+H]+=588

HPLC (Method 5): retention time=1.55 min

EXAMPLE 545

C₂₈H₄₀N₄O₅S×HCl (581.17)

[M+H]+=545

HPLC (Method 4): retention time=3.3 min

EXAMPLE 546

C₂₇H₄₅N₅O₅S×2HCl (624.66)

[M+H]+=552

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.01, Rf value=0.25

EXAMPLE 547

C₂₆H₄₃N₅O₅S×HCl (574.18)

[M+H]+=538

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.01, Rf value=0.10

EXAMPLE 548

C₂₉H₄₃N₅O₅S×HCl (610.21)

[M+H]+=574

DC: silica gel, dichloromethane/methanol 9:1, Rf value=0.25

EXAMPLE 549

C₃₁H₄₄N₄O₅S×HCl (621.23)

[M+H]+=585

HPLC (Method 12): retention time=3.0 min

EXAMPLE 550

C₂₈H₄₃N₅O₅S×HCl (598.20)

[M+H]+=562

DC: silica gel, dichloromethane/methanol 9:1, Rf value=0.14

EXAMPLE 551

C₂₉H₄₂N₄O₅S×HCl (595.19)

[M+H]+=559

DC: silica gel, dichloromethane/methanol/ammonia 9:1:0.1, Rf value=0.32

EXAMPLE 552

C₂₈H₄₀N₄O₆S (560.71)

[M+H]+=561

HPLC (Method 9): retention time=1.66 min

EXAMPLE 553

C₂₇H₃₅N₅O₆S (557.66)

[M+H]+=558

HPLC (Method 9): retention time=1.64 min

EXAMPLE 554

C₂₆H₃₈FN₅O₅S (551.68)

[M+H]+=552

HPLC (Method 6): retention time=2.30 min

EXAMPLE 555

C₂₆H₃₆N₆O₅S (544.67)

[M+H]+=545

HPLC (Method 6): retention time=1.48 min

EXAMPLE 556

C₂₆H₃₅N₅O₅S (529.65)

[M+H]+=530

HPLC (Method 9): retention time=1.61 min

EXAMPLE 557

C₂₃H₂₉N₅O₅S (487.57)

[M+H]+=488

HPLC (Method 9): retention time=1.53 min

EXAMPLE 558

C₂₇H₄₇N₅O₅S×2HCl (626.68)

[M+H]+=554

HPLC (Method 7): retention time=1.61 min

EXAMPLE 559

C₂₇H₄₇N₅O₅S×2HCl (626.68)

[M+H]+=554

HPLC (Method 7): retention time=1.61 min

EXAMPLE 560

C₂₈H₄₇N₅O₅S×CH₂O₂ (611.80)

[M+H]+=566

HPLC (Method 9): retention time=1.33 min

EXAMPLE 561

C₂₅H₄₁N₅O₅S×2HCl (596.61)

[M+H]+=524

HPLC (Method 12): retention time=2.3 min

EXAMPLE 562

C₂₆H₄₃N₅O₅S×2HCl (610.64)

[M+H]+=538

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.2, Rf value=0.53

EXAMPLE 563

C₂₉H₄₂N₄O₅S×HCl (595.19)

[M+H]+=559

HPLC (Method 12): retention time=2.8 min

EXAMPLE 564

C₂₆H₃₈N₄O₅S×C₂HF₃O₂ (632.69)

[M+H]+=519

HPLC (Method 9): retention time=1.61 min

EXAMPLE 565

C₂₉H₄₀N₄O₅S (556.72)

[M+H]+=557

HPLC (Method 9): retention time=1.69 min

EXAMPLE 566

C₃₀H₄₂N₄O₆S (586.74)

[M+H]+=587

HPLC (Method 9): retention time=1.74 min

EXAMPLE 603

C₂₉H₄₉N₅O₅S×2HCl (652.72)

[M+H]+=580

HPLC (Method 10): retention time=1.11 min

EXAMPLE 604

C₃₀H₅₁N₅O₅S×2HCl (666.74)

[M+H]+=594

HPLC (Method 10): retention time=1.11 min

EXAMPLE 605

C₂₉H₄₂N₄O₅S×HCl (595.19)

[M+H]+=559

HPLC (Method 12): retention time=3.1 min

EXAMPLE 606

C₂₉H₄₂N₄O₅S×HCl (595.19)

[M+H]+=559

DC: silica gel, dichloromethane/methanol/ammonia 8:2:0.01, Rf value=0.68

EXAMPLE 631

C₂₇H₄₄N₄O₆S×HCl (589.19)

[M+H]+=553

HPLC (Method 5): retention time=1.35 min

EXAMPLE 632

C₂₅H₄₂N₄O₆S×HCl (563.15)

[M+H]+=527

HPLC (Method 5): retention time=1.38 min

EXAMPLE 633

C₂₇H₄₄N₄O₆S×HCl (589.19)

[M+H]+=553

HPLC (Method 5): retention time=1.35 min

EXAMPLE 634

C₂₅H₄₂N₄O₆S×HCl (563.15)

[M+H]+=527

HPLC (Method 5): retention time=1.32 min

The following compounds were prepared analogously to Example 130:

EXAMPLE 567

C₂₆H₄₄N₄O₄S×2C₂HF₃O₂ (736.76)

[M+H]+=509

HPLC (Method 6): retention time=1.36 min

EXAMPLE 568

C₂₈H₄₁N₃O₄S×C₂HF₃O₂ (629.73)

[M+H]+=516

HPLC (Method 6): retention time=1.77 min

The following compounds were prepared analogously to Example 136:

EXAMPLE 569

C₂₅H₄₂N₄O₄S₂×C₂HF₃O₂ (640.78)

[M+H]+=527

HPLC (Method 6): retention time=1.35 min

EXAMPLE 570

C₂₇H₃₉N₃O₄S₂ (533.75)

[M+H]+=534

HPLC (Method 6): retention time=1.74 min

The following compound was prepared analogously to Example 138:

EXAMPLE 571

C₂₆H₃₈N₄O₅S×CH₂O₂ (564.70)

[M+H]+=519

HPLC (Method 6): retention time=2.33 min

EXAMPLE 572

572a)

A mixture of 88.0 mg (0.167 mmol) of 569, 0.15 g (0.61 mmol) of 70% m-chloroper-benzoic acid (Fluka) and 3 ml dichloromethane is stirred for 30 minutes at ambient temperature and then evaporated to dryness in vacuo. The residue is dissolved in methanol and membrane-filtered. The product is then obtained by preparative HPLC from the filtrate.

C₂₅H₄₂N₄O₈S₂ (590.76)

[M+H]+=591

572b)

A mixture of 90.0 mg (0.15 mmol) of the product of 572a, 20.0 mg Raney nickel and 10 ml THF is stirred for one hour in the autoclave at ambient temperature. Then the catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The crude product thus obtained is purified by preparative HPLC.

C₂₅H₄₂N₄O₆S₂×CH₂O₂ (604.78)

[M+H]+=559

HPLC (Method 6): retention time=1.33 min

EXAMPLE 573

573a)

573a is prepared analogously to 1f from 2.16 g (7.50 mmol) of the product of 121b, 1.20 g (7.50 mmol) of N-Boc-ethylenediamine (Fluka), 3.14 ml (22.50 mmol) of triethylamine and 2.41 g (7.50 mmol) of TBTU in 28 ml THF and 4 ml DMF.

C₁₉H₃₁N₃O₆S (429.53)

DC: silica gel, dichloromethane/ethanol 19:1, Rf value=0.35

573b)

573b is prepared analogously to 28d from 2.70 g (6.29 mmol) of the product of 573a and 7 ml TFA in 50 ml dichloromethane.

C₁₄H₂₃N₃O₄S (329.42)

DC: silica gel, dichloromethane/ethanol 9:1, Rf value=0.15

573c)

Example 573 is prepared analogously to 1f from 0.119 g (0.50 mmol) of 4-(2-diethylaminoethoxy)-benzoic acid (J. Med. Chem. 14, 1971, 836-842), 0.165 g (0.50 mmol) of the product of 573b, 0.21 ml (1.50 mmol) of triethylamine and 0.16 g (0.50 mmol) of TBTU in 7 ml THF and 1 ml DMF.

C₂₇H₄₀N₄O₆S×HCl (585.16)

HPLC (Method 5): retention time=1.44 min

The following compounds were prepared analogously to Example 573:

EXAMPLE 574

C₂₆H₃₆N₄O₅S×HCl (553.11)

[M+H]+=517

HPLC (Method 5): retention time=1.40 min

EXAMPLE 607

C₂₈H₄₀N₄O₅S×HCl (581.17)

[M+H]+=545

HPLC (Method 12): retention time=3.51 min

EXAMPLE 635

635a)

A mixture of 0.78 g (4.98 mmol) of monomethylmalonate potassium salt (Fluka), 0.52 g (5.47 mmol) of magnesium chloride and 30 ml THF is stirred for four hours at 50° C. A second mixture of 1.00 g (3.32 mmol) of the product of 22c, 0.65 g (3.98 mmol) of CDI and 20 ml THF is stirred first for one hour at RT and then added to the first mixture. The mixture is stirred overnight at RT and then the precipitate formed is filtered off. The filtrate is evaporated to dryness in vacuo. The crude product thus obtained is triturated with water, filtered off and dried at 45° C. in the vacuum dryer.

C₁₆H₂₃NO₆S (357.42)

[M+H]+=358

HPLC (Method 9): retention time=2.19 min

635b)

635b is prepared analogously to 60a from 0.47 ml (4.07 mmol) of 1-methyl-4-piperidone (Fluka), 0.76 g .(4.07 mmol) of (R)-3-(Boc-amino)-pyrrolidine (Fluka), 1.72 g (8.13 mmol) of sodium triacetoxyborohydride and 0.23 ml (4.07 mmol) of acetic acid in 10 ml dichloromethane.

C₁₅H₂₉N₃O₂ (283.41)

[M+H]+=284

635c)

635c is prepared analogously to 38f from 0.90 g (3.18 mmol) of the product of 635b and 5.0 ml (10.00 mmol) of lithium aluminium hydride (2M in THF) in 15 ml THF.

C₁₁H₂₃N₃ (197.32)

[M+H]+=198

635d)

A mixture of 0.56 g (1.58 mmol) of the product of 635a, 0.54 g (2.73 mmol) of the product of 635c and 5 ml of toluene is heated to 120° C. for 24 hours. Then the reaction mixture is evaporated to dryness in vacuo. The crude product thus obtained is purified by preparative HPLC.

C₂₆H₄₂N₄O₅S (522.70)

[M+H]+=523

HPLC (Method 9): retention time=1.33 min

The following Examples describe pharmaceutical formulations which contain as active substance any desired compound of general formula I:

EXAMPLE I Dry Ampoule with 75 mg of Active Compound Per 10 ml Composition:

Active compound 75.0 mg Mannitol 50.0 mg Water for injection ad 10.0 ml

Production:

Active compound and mannitol are dissolved in water. The charged ampoules are freeze dried. Water for injection is used to dissolve to give the solution ready for use.

EXAMPLE II Tablet with 50 mg of Active Compound Composition:

(1) Active compound 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate  2.0 mg 215.0 mg 

Production:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is admixed to the dry granules. Tablets are compressed from this mixture, biplanar with a bevel on both sides and dividing groove on one side.

Diameter of the tablets: 9 mm.

EXAMPLE III Tablet with 350 mg of Active Compound Composition:

(1) Active compound 350.0 mg (2) Lactose 136.0 mg (3) Maize starch  80.0 mg (4) Polyvinylpyrrolidone  30.0 mg (5) Magnesium stearate  4.0 mg 600.0 mg

Production:

(1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is admixed to the dry granules. Tablets are compressed from this mixture, biplanar with a bevel on both sides and dividing groove on one side.

Diameter of the tablets: 12 mm.

EXAMPLE IV Capsule with 50 mg of Active Compound Composition:

(1) Active compound 50.0 mg (2) Maize starch dried 58.0 mg (3) Lactose powdered 50.0 mg (4) Magnesium stearate  2.0 mg 160.0 mg 

Production:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.

This powder mixture is packed into hard gelatine two-piece capsules of size 3 in a capsule-filling machine.

EXAMPLE V Capsules with 350 mg of Active Compound Composition:

(1) Active compound 350.0 mg (2) Maize starch dried  46.0 mg (3) Lactose powdered  30.0 mg (4) Magnesium stearate  4.0 mg 430.0 mg

Production:

(1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous stirring.

This powder mixture is packed into hard gelatine two-piece capsules of size 0 in a capsule-filling machine.

EXAMPLE VI Suppositories with 100 mg of Active Compound 1 Suppository Comprises:

Active compound 100.0 mg Polyethylene glycol (M.W. 1500) 600.0 mg Polyethylene glycol (M.W. 6000) 460.0 mg Polyethylene sorbitan monostearate 840.0 mg 2000.0 mg  

1. A compound of the formula I

wherein A denotes a bond, C₁₋₄-alkylene or —CH₂—C(O), B denotes a bond, C₁₋₃-alkylene, —O or —C(O), D denotes a group of general formulae II

Y denotes a C₁₋₆-alkylene group optionally substituted by the group R², wherein a methylene group may additionally be replaced by Y¹ and Y¹ denotes —O, —S, —S(O), —N(R²), —N(R²)—C(O), —C(O)—N(R²), —C(O), —CH(aryl), C₃₋₆-cycloalkylene or —S(O)₂—, R¹ denotes C₃₋₇-cycloalkyl or aryl, heteroaryl or aryl-C₁₋₃-alkyl, each of which may be substituted by one, two, three or four groups R^(1.1), while the groups R^(1.1) may be identical or different and R^(1.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, F₃C, HO, C₁₋₃-alkyl-O or C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, R² denotes H or C₁₋₃-alkyl, while each methylene group may be substituted by up to two and each methyl group may be substituted by up to three fluorine atoms, or also denotes H₃C—C(O), R³ denotes a) C₁₋₆-alkylene, b) a C₃₋₆-cycloalkylene group mono-, di or trisubstituted by R^(3.1), c) a C₅₋₇-cycloalkenylene group mono- or disubstituted by R^(3.1) which is fused to a phenyl ring via the unsaturated bond, d) —N(R²), e) an arylene group mono- or disubstituted by R^(3.1), f) a heteroarylene group mono- or disubstituted by R^(3.1), g) a saturated 4- to 7-membered heterocyclic ring mono- or disubstituted by R^(3.1), h) an unsaturated 5- to 7-membered heterocyclic ring mono- or disubstituted by R^(3.1), which is fused to one or two phenyl rings via the unsaturated bonds, or i) a saturated 8- to 10-membered aza-heterobicyclic group mono- or disubstituted by R^(3.1), while the groups R^(3.1) may be identical or different in each case and R^(3.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, HO, C₁₋₃-alkyl-O or C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, or R³ also denotes —O, if B does not denote the group —O—, R⁴ denotes a) —O, b) —C(O)O, c) —C(O)NR², d) —NR² e) —NR²—NR², f) C₃₋₇-cycloalkylene, g) C₁₋₆-alkylene, h) an arylene group mono- or disubstituted by R^(4.1), i) a heteroarylene group mono- or disubstituted by R^(4.1), j) a 4- to 7-membered saturated heterocyclic ring mono- or disubstituted by R^(4.1), k) a saturated 8- to 10-membered diaza-heterobicyclic group mono- or disubstituted by R^(4.1), l) a 5- to 7-membered unsaturated heterocyclic ring mono- or disubstituted by R^(4.1), which is fused to one or two phenyl rings via the unsaturated bonds, or m) a saturated 9- to 11-membered diaza-spirocyclic group, while the groups R^(4.1) may in each case be identical or different and R^(4.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, HO, C₁₋₃-alkyl-O or C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, R⁵ denotes H, HO, C₁₋₈-alkyl, a C₃₋₇-cycloalkyl group optionally substituted by C₁₋₃-alkyl, H₂N, C₁₋₄-alkyl-NH, (C₃₋₆-cycloalkyl)-NH, (C₁₋₄-alkyl)₂N, (C₁₋₄-alkyl)(C₃₋₆-cycloalkyl)N, (cyclopropylmethyl)(methyl)N, H₂N—C(O), a phenyl group mono- or disubstituted by R^(5.1), a heteroaryl group mono- or disubstituted by R^(5.1) or a 4- to 7-membered saturated heterocyclic ring mono- or disubstituted by R^(5.1), while the groups R^(5.1) may in each case be identical or different and R^(5.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, HO, C₁₋₃-alkyl-O, (C₁₋₃-alkyl)₂N or C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, or a physiologically acceptable salt thereof.
 2. A compound of the formula I according to claim 1, wherein A denotes a bond, C₁₋₄-alkylene or —CH₂—C(O), B denotes a bond, C₁₋₂-alkylene, —O or —C(O), D denotes a group of general formula II

Y denotes C₁₋₄-alkylene or a group selected from

R¹ denotes aryl or heteroaryl, each of which may be substituted by one, two, three or four groups R^(1.1), while the groups R^(1.1) may be identical or different and R^(1.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, F₃C, HO, C₁₋₃-alkyl-O or C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, R² denotes H, H₃C, H₅C₂, isopropyl, F₃C—CH₂, F₂CH—CH₂ or FH₂C—H₂C, R³ denotes C₁₋₄-alkylene, —N(R²) or a group selected from

wherein R^(3.1) denotes H, F, Cl, Br, I, C₁₋₃-alkyl, HO, C₁₋₃-alkyl-O or C₁₋₃-alkyl-O—C₂₋₄-alkylene-O—, or R³ also denotes —O, if B does not denote the group —O—, R⁴ denotes C₁₋₄-alkylene, C₃₋₇-cycloalkylene, —O or a group selected from

R⁵ denotes H, C₁₋₈-alkyl, C₃₋₇-cycloalkyl, HO, (C₁₋₃-alkyl)-O, (C₁₋₄-alkyl)-NH, (C₃₋₆-cycloalkyl)-NH, (C₁₋₄-alkyl)₂N, (C₁₋₄-alkyl)(C₃₋₆-cycloalkyl)N, (cyclopropylmethyl)(methyl)N, H₂N—C(O), or R⁵ denotes a group selected from

or a physiologically acceptable salt thereof.
 3. A compound of the formula I according to claim 1, wherein A denotes a bond, C₁₋₃-alkylene or —CH₂—C(O), B denotes a bond, C₁₋₂-alkylene, —O or —C(O), D denotes a group of general formula II

Y denotes a group selected from

R¹ denotes a group selected from

R² denotes H, H₃C, H₅C₂ or FH₂C—H₂C, R³ denotes C₁₋₄-alkylene, —NH, —N(CH₃) or a group selected from

or R³ also denotes —O, if B does not denote the group —O—, R⁴ denotes C₁₋₄-alkylene, C₃₋₇-cycloalkylene, —O or a group selected from

R⁵ denotes H, HO, C₁₋₅-alkyl, C₃₋₅-cycloalkyl, H₂N, (C₁₋₂-alkyl)-NH, (C₃₋₆-cycloalkyl)-NH, (C₁₋₂-alkyl)₂N, (C₁₋₄-alkyl)(C₃₋₆-cycloalkyl)N, (cyclopropylmethyl)(methyl)N, H₂N—C(O), or R⁵ denotes a group selected from

or a physiologically acceptable salt thereof.
 4. A compounds of the formula I according to claim 1, wherein A, B, D, Y, R², R³, R⁴ and R⁵ are defined as in claim 1 and R¹ denotes the group

or a physiologically acceptable salt thereof.
 5. A compound of the formula I according to claim 1, wherein A, B, D, Y, R², R³, R⁴ and R⁵ are defined as in claim 1 and R¹ denotes the group

or a physiologically acceptable salt thereof.
 6. A compound of the formula I according to claim 1, wherein A, B, R¹, R³, R⁴ and R⁵ are defined as in claim 1 and -D-Y— together denote a group selected from

and R² denotes H or C₁₋₃-alkyl, or a physiologically acceptable salt thereof.
 7. A compound of the formula I according to claim 1, selected from the group consisting of: Example Structure  (1)

 (2)

 (3)

 (4)

 (5)

 (6)

 (7)

 (8)

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 (10)

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(100)

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(649)

(650)

or a physiologically acceptable salt thereof.
 8. A pharmaceutical composition comprising a compound according to claim 1, 2, 3, 4, 5, 6 or 7 and a pharmaceutically acceptable carrier or diluent.
 9. A method for treating acute pain, visceral pain, neuropathic pain, inflammatory pain, receptor-mediated pain, tumour pain and headache, which comprises administering, to a host suffereing from such condition, a therapeutically effective amount of a compound according to claim 1, 2, 3, 4, 5, 6 or
 7. 